Prevalence and risk factors
Endometriosis is one of the most common benign gynaecological disorders but the exact prevalence is difficult to determine because of the need for a surgical procedure to diagnose the disease (3).
Endometriosis is found predominantly in women of reproductive age but has been reported in young adolescents and in postmenopausal women receiving hormonal replacement therapy (3). Estimates of the prevalence of endometriosis among women of reproductive age vary between 2% and 10%, but this prevalence can rise to 30-50% in women with infertility and/or pain (4, 5). The World Endometriosis Research Foundation EndoCost study has shown that the healthcare costs of endometriosis are similar to the costs for diabetes mel- litus, Crohn's disease, and rheumatoid arthritis (4). Apart from the economic burden, endometriosis has a significant effect on various aspects of women's lives, including their social and sexual relationships, work, and study (2).Various factors such as genetic profile, inflammation, menstrual cyclicity, and immunological factors have been suggested to play a role in the pathophysiology of endometriosis (6). From epidemiological studies, nulliparity and short, heavy menstrual cycles are the most consistently reported risk factors (3). An overview of risk factors for endometriosis is presented is Table 45.1.
Consistent evidence exists that a family history of endometriosis is more common in women with endometriosis and that the risk of endometriosis is higher in women whose mother or sisters have the disease (3, 7). Twin studies have demonstrated a higher concordance of endometriosis in monozygotic versus dizygotic twins with the proportion of disease variance due to genetic factors estimated at around 52% (9). Studies in rhesus monkeys allowed construction of a detailed multigenerational pedigree with a significantly higher kinship coefficient for affected animals and higher risk for endometriosis in full siblings, underlining the familial aggregation of endometriosis (10).
Meta-analysis of eight genome-wide association studies in patients with endometriosis has shown evidence of a robust association of endometriosis with six risk loci: rs12700667 on 7p15.2, rs7521902 near WNT4 (wingless-type MMYV integration family member 4), rs10859871 near VEZT (vezatin), rs1537377 near CDKN2B-AS1 (cyclin-dependent kinase inhibitor 2b antisense RNA), rs7739264 near ID4 (inhibitor of DNA binding 4), and rs13394619 in GREB1 (growth regulation by oestrogen in breast cancer 1) (11). The 7p15.2 region contains several potential candidate genes such as NFE2L3 (nuclear factor erythroid derived 2-like 3), MIR148A (microRNA 148a), HOXA10 (homeobox A10), and HOXA11 (homeobox A11) (11). NFE2L3 protein is a transcription factor suggested to be involved in cell differentiation, inflammation, and carcinogenesis (11). MicroRNA 148a possibly plays a role in the Wnt∕β-catenin signalling pathway which has an important role in communication between epithelial and stromal cells in endometrium, fibrogenesis, and sex hormone homeostasis regulation (11). HOXA10 and HOXA11 are members of the homeobox A family of transcription factors that play a role in uterine development (11). WNT4 encodes a member of the wingless-type MMTV integration site family, which is important for the development of the female reproductive tract and for steroidogenesis (12). VEZT encodes an adherens junction transmembrane protein, a putative tumour suppressor gene targeting cell migration and invasion genes, growth genes, cellular adhesion genes, and a functionally validated cell cycle progression gene called TCF19 (transcription factor 19) (11). CDKN2B- AS1 has been shown to be involved in the regulation of p15, p16-INK4a, and p14ARF
Table 45.1 Risk factors for endometriosis
| Risk factor | Description of association | Strength of association |
| Socioeconomic status | Higher socioeconomic status increases risk | Limited |
| Family history | Relatives with endometriosis increase risk for endometriosis | Consistent |
| Constitutional factors | ||
| Age at menarche | Early age increases risk | Consistent |
| Cycle length | Shorter cycle increases risk | Consistent |
| Menstrual flow | Longer flow increases risk | Limited |
| Dysmenorrhea | Strong predictor | Consistent |
| Parity | Higher parity decreases risk | Consistent |
| Weight and BMI | Lower BMI increases risk | Limited |
| Height | Taller height increases risk | Limited |
| Lifestyle factors | ||
| Physical activity | Regular physical activity decreases risk | Limited |
| Diet | Possible protective effect of vegetables and fruits. Possible unfavourable effect of red meat, dairy products and unsaturated fats | Limited |
| Smoking | No evidence for association | Limited |
| Alcohol | Use of alcohol increases risk | Limited |
| Caffeine | No evidence for association | Limited |
| Contraception | Protective effect of combined oral contraceptives | Limited |
| Environmental factors | ||
| PCB exposure | Exposure to PCB increases risk | Limited |
| Dioxin exposure | Exposure to dioxins increases risk | Limited |
| Comorbidities | ||
| Possibly increase risk | Limited | |
| Immunological diseases | Possibly increase risk | Limited |
| Cardiovascular diseases | Possibly increase risk | Limited |
BMI, body mass index; GI, gastrointestinal; PCB1 polychlorinated biphenyl.
Source data from Missmer SA, Cramer DW. Obstet Gynecol Clin North Am 2003;30:1-19; Vigano et al. Best Pract Res Clin Obstet Gynaecol 2004;18:177-200; Parazzini et al. EurJ Obstet Gynecol Reprod Bio12017;209:3-7.
expression which are all recognized tumour suppressor proteins (12). Rs7739264 is located in an intronic region of IncRNA RP1- 167F1.2 (794 bp), of which the biological function remains to be discovered. It is located 52 kb downstream of ID4, an ovarian oncogene that is overexpressed in most primary ovarian cancers (11). GREB1 encodes an early-response gene in the oestrogen receptor-regulated pathway that is involved in hormone-dependent breast cancer (12).
Large genome-wide linkage studies, including more than 1300 families, have identified three linkage regions of endometriosis: on chromosome 10q26, chromosome 20p13, and chromosome 7p13- 15 (13). The linkage region on chromosome 10q26 has been studied in more detail and identified a possible role for the CYP2C19 gene, which is involved in drug and oestrogen metabolism (13). Three candidate genes for the linkage region on chromosome 7p13-15 have been suggested: INHBA, SFRP4, and HOXA10, which play roles in endometrial development (13). Functional studies and sequencing of the genes in these linkage regions are needed to elucidate their precise role and determine the effects of the variants in underlying pathways (13).