PLIEGO DE CONDICIONES PARTICULARES ESTUDIO DE SEGURIDAD Y SALUD PARTE

Genetic and environmental factors contribute to endometriosis risk and the disease is inherited as a complex trait (Bischoff and Simpson, 2004, Kennedy, 1999, Stefansson et al., 2002). Gene markers associated with endometriosis have been reported but the results have generally not been replicated in subsequent studies. The variability between studies has also led to concerns about estimates of the genetic contribution to disease risk. Studies in Australian twins, Icelandic populations and rhesus macaques (Treloar et al., 1999, Stefansson et al., 2002, Zondervan et al., 2002) have provided strong evidence for disease heritability.

Large genome wide association studies (GWAS) have provided a powerful approach to discover genes influencing the risk of many common diseases. This method involves genotyping DNA samples with representative single nucleotide polymorphisms from across the genome and allele frequencies compared between cases and controls. A study in Japanese women (1,423 cases and 1,318 controls) reported a significant association with SNPs in the noncoding RNA CDKN2BAS on chromosome 9p21.3 (Uno et al., 2010). The International ENDOGENE study represents collaboration between research groups in the United Kingdom, USA and Australia whose main aim was to identify variants that influence susceptibility to endometriosis. This study which recruited 2,270 cases and 1,870 controls from Australia and 924 cases and 5,190 controls from the United Kingdom, identified a significant association in an intergenic region on 7p15.2. They also replicated evidence for an association near the WNT4 gene on 1p36.12, previously reported in the Japanese study (Uno et al., 2010). Data from this study provides independent evidence for a genetic contribution to disease risk, supporting results from earlier family-based studies (Stefansson et al., 2002, Treloar et al., 1999). These results also demonstrated stronger genetic loading of moderate to severe (stage III and IV) endometriosis compared to minimal to mild (stage I and II). The number of variants discovered in GWAS is strongly correlated with the experimental sample size

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(Visscher et al., 2012). For each disease, doubling the study size doubles the number of genes/regions identified above a given threshold. It has been recommended that increasing the sample size for genetic studies in endometriosis will increase the number of markers and gene regions associated with disease risk (Rogers et al., 2013). Results also need to be replicated to confirm associations and to establish differences in gene expression to identify the specific genes and pathways contributing to disease risk.

1.5.2 Demographic risk factors

Endometriosis affects women of reproductive age. A study in women under 50 suggested that the frequency of endometriosis increases with age until menopause although other studies have not confirmed this (Houston et al., 1988). Age at diagnosis instead of age at onset is an assumption that due to the absence of fluctuating levels of oestrogen and progesterone, the condition is absent in girls before menarche. Endometriosis may be symptomatic after menopause if there is a resurgence of endogenous hormonal stimulation or if the use of exogenous hormones stimulates endometriosis (Ranney B, 1977). This suggests that sex steroid hormones play a role in the initiation and spread of endometriosis.

A greater frequency of endometriosis among women of higher social economic class has been reported (Arumugam and Templeton, 1990). This has been linked to their reproductive history as this groups of women tend to have fewer and later pregnancies than those from lower socio-economic groups (Williams and Pratt, 1977). It has been suggested that a lower incidence is in blacks is not because of race, but because of endemic poverty among a large portion of the black population (Chatman, 1976). However, poverty could create an apparent differential in disease occurrence across racial groups because of differential access to specialised medical care and the existence of a prejudicial diagnostic aspect based on what is ‘known’ about racial susceptibility to endometriosis. Differences in the incidence of endometriosis can also be attributed to the relative availability of laparoscopy for the diagnosis of pelvic conditions (Molgaard et al., 1985). This can account for the comparatively low

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occurrence in certain racial and socio-economic groups, with the less affluent being constrained in their access to and utilisation of medical resources for the complete investigation of pain, infertility or both.

1.5.3 Menstrual factors

The correlation between menstrual history and risk of pelvic endometriosis is poorly understood. Some studies have suggested that women with early menarche, short and heavy menstrual cycles are at a higher risk of developing endometriosis (Cramer and Missmer, 2002, Parazzini et al., 1995, Cramer et al., 1986). This has been attributed to the fact that the potential for contamination of the pelvic cavity by refluxed menstrual debris is higher in these women hence a high risk of implantation of viable endometrial cells. It has however been noted that evidence for this is very inconsistent with interpretation of some of these findings being biased (Mangtani and Booth, 1993).

1.5.4 Oral contraceptive use

Oral contraceptives are used in the treatment of endometriosis. They do not cure the disease but instead work by down-regulating the endometrium, hence supressing menstruation, reducing pain and shrinking the ectopic implants or preventing the existing ones from growing any bigger. Information regarding the relation between oral contraceptive (OC) use and endometriosis risk remains controversial (Cramer and Missmer, 2002). A study to establish prevalence and associated risk factors in 504 women reported a lower risk among OC users (OR 0.5, 95% CI 0.2-0.90) (Sangi- Haghpeykar and Poindexter, 1995). The same has been reported in another large study where the rate of disease was lower in current/recent users as compared to those who have never used (relative risk 0.4, 95% CI 0.2-0.7) (Vessey et al., 1993). It was also reported in the same study that women who had stopped the pill for more than 2 years were at a higher risk (RR 1.8, 9.5% CI 1.0-3.1).

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1.5.5 Family History

A familial risk for developing endometriosis has been proposed (Lamb et al., 1986, Moen and Magnus, 1993, Moen and Schei, 1997, Malinak et al., 1980, Simpson et al., 1980). For example high prevalence in relatives of affected women has been reported (Moen and Magnus, 1993). A wealth of genetic factors have been anticipated to be linked to increased susceptibility to endometriosis (Guidace and Kao, 2004) but common genetic markers for endometriosis have not yet been identified. Further studies however need to be conducted in order to establish the role heredity plays as a risk factor for endometriosis.

1.5.6 Environmental factors

Exposure to some environmental toxins are thought to be associated with endometriosis e.g. dioxin (2, 3, 7, 8 tetrachlorodibenzo-p-dioxin) (Rier et al., 1993). It is thought that dioxin promotes the development of endometriosis by interfering with immune-mediated mechanisms, more specifically by stimulating the production of pro-inflammatory cytokines.

1.5.7 Diet and other lifestyle factors

Alcohol intake and diet high in fat have been suggested as risk factors of endometriosis (Houston, 1984, Vessey et al., 1993, Cramer et al., 1986). An association between tobacco smoking and endometriosis has been reported in some studies (Aban et al., 2007, Chapron et al., 2010, Vidal et al., 2006). Smoke compounds lead to the disruption of oestradiol synthesis possibly reducing the risk (Vidal et al., 2006). However data is limited and further studies need to be conducted in order to establish whether diet, nutrition, alcohol and smoking could be risk factors for endometriosis.

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