While there are likely differences in genotypes underlying each phenotype, the specific correlating genotypes have not yet been identified. These phenotypes are prevalent at different levels in different population demographics, suggesting different allelic frequencies across populations (in terms of race, ethnicity, and nationality).Polymorphisms in the ESR1 gene have been commonly associated with severe dysmenorrhea. Variant genotypes in the metabolic genes such as CYP2D6 and GSTM1 have been similarly been correlated with an increased risk of severe menstrual pain, but not with moderate or occasional phentoypes.The occurrence and frequency of secondary dysmenorrhea (SD) has been associated with different alleles and genotypes of those with underlying pathologies, which can affect the pelvic region or other areas of the body. Individuals with disorders may have genetic mutations related to their diagnoses which produce dysmenorrhea as a symptom of their primary diagnosis. It has been found that those with fibromyalgia who have the ESR1 gene variation Xbal and possess the Xbal AA genotype are more susceptible to experiencing mild to severe menstrual pain resulting from their primary pathology. Commonly, genetic mutations which are a hallmark of or associated with specific disorders can produce dysmenorrhea as a symptom which accompanies the primary disorder. In contrast with secondary dysmenorrhea, primary dysmenorrhea (PD) has no underlying pathology. Genetic mutation and variations have therefore been thought to underlie this disorder and contribute to the pathogenesis of PD. There are multiple single-nucleotide polymorphisms (SNP) associated with PD.
This gene encodes a protein essential for the regulation of immunity and inflammation.15 While the mechanism of how it influences PD has yet to be discovered, it is assumed that possible mutations in IL1A or genes which interact with it impact the regulation of inflammation during menstruation. These mutations may therefore affect pain responses during menstruation which lead to the differing phenotypes associated with dysmenorrhea. Two additionally well studied SNPs which are suspected to contribute to PD were found in ZM1Z1 (the mutant allele called rs76518691) and NGF (the mutant allele called rs7523831). Both ZMIZ1 and NGF are associated with autoimmune responses and diseases, as well as pain response. The implication of these genes impacting Dysmenorrhea is significant as it suggests mutations which affect the immune system (specifically the inflammatory response) and pain response may also be a cause of primary dysmenorrhea. Mechanism
The underlying mechanism of primary dysmenorrhea is the contractions of the muscles of the uterus which induce a local ischemia.During an individuals menstrual cycle, the endometrium thickens in preparation for potential pregnancy. After ovulation, if the ovum is not fertilized and there is no pregnancy, the built-up uterine tissue is not needed and thus shed. Prostaglandins and leukotrienes are released during menstruation, due to the build up of omega-6 fatty acids. Release of prostaglandins and other inflammatory mediators in the uterus cause the uterus to contract and can result in systemic symptoms such as nausea, vomiting, bloating and headaches or migraines. Prostaglandins are thought to be a major factor in primary dysmenorrhea.