**5.3 Polymorphisms**

Some genetic polymorphisms, involved in sex steroids biosynthesis and metabolism, may be reasonably associated with an increased risk of endometriosis. Specific genes with polymorphisms have been investigated for an association with endometriosis. Some association studies implicated GALT (a gene involved in galactose metabolism) and GSTM1 and NAT2 (genes encoding for the detoxification enzymes) as possible disease susceptibility genes. Recent finding have added to the evidence for the involvement of GSTM1 and NAT2, but have cast doubt on the role of GALT. The CDKN1A gene codon 31-arginine/serine polymorphism is not associated with endometriosis. Polymorphisms of the arylhydrocarbon receptor (AHR) gene and related genes were examined, and in at least one study, no association was found.

The endometriosis regresses after menopause or ovariectomy, suggesting it could depend on the production and metabolism of sex steroids (Kitawaki et al., 2002): high concentrations of estrogens were found in the endometriotic lesions, which grow and regress in an oestrogen-dependent way.

The inheritable susceptibility to endometriosis justifies the growing interest in identifying genes and/or genetic polymorphisms that could lead to an increased risk of disease. Identifying these polymorphisms may open to their use as genetic biomarkers of endometriosis **(**Vietri et al., 2007a, 2007b). Some genetic polymorphisms, involved in sex steroids biosynthesis and metabolism, may be reasonably associated with an increased risk of endometriosis, like progesterone receptor (PR), AR, oestrogen receptor (AR), 17betahydroxysteroid dehydrogenase type 1 (HSD17B1), cytochrome P450 subfamily 17 (CYP17) and cytochrome P450 subfamily 19 (CYP19) (Guo, 2006). No doubt this list is likely to increase over the years. The most widely used approach for the identification of endometriosis-predisposing genetic polymorphisms are the genetic association studies, by which genetic susceptibility polymorphisms are identified through the identification and assessment of the difference in allele/genotype frequencies between patients and control subjects.

The **CYP17 genotype** contains a single nucleotide T>C polymorphism situated 34bp upstream of the translation initiation site. C allele may have great promoter activity, increasing the transcription of P450c17 alpha enzyme. This effect amplifies the production of precursor androgens that are subsequently converted to estrogens. In fact, C allele is associated with high levels of estradiol in young women. CYP19 gene lies on chromosome 15 and encodes cytochrome P450, a major component of aromatase. Aromatase is a key enzyme in the conversion of androgens to estrogens, and mediates the rate-limiting step in the metabolism of C19 androgens to estrogens. Different polymorphisms of CYP19 are present in the gene and have been related to variations of aromatase activity (Gennari et al., 2004). A silent SNP, C1558T, corresponding to the 3' untraslated region of the mRNA, has been correlated to the level of aromatase mRNA in breast tumour cells. Another polymorphism, GA at Val80, has been previously associated with breast cancer risk. Few studies have been published on the association between CYP17 T>C polymorphism with risk of endometriosis, showing controversial data. Some studies connected C1558T polymorphism with endometriosis risk (Huber et al., 2005), while no report relates Val80 SNP to endometriosis.

The **CYP19 genotype** may play a role in increased risk of endometriosis lying on an environmental and genetic background. The polymorphisms of CYP19 are significantly represented in Val80 and C1558T in patients affected with endometriosis. Despite endometriosis is a multifactorial disease, identifying Val80 and C1558T polymorphisms of CYP19 could help to comprehend the mechanisms of endometriosis. The assessment of these polymorphisms could help to anticipate the diagnosis or expect it in asymptomatic women to elaborate a follow up program. Other than that, a follow up by ultrasound and blood markers could be proposed in these patients, in order to define unclear symptoms such as dysmenorrhoea and chronic pelvic pain.
