will prevent or treat TMD despite the existence of systematic reviews of the subject which state that there is no evidence for such practices, and the vast majority of opinion being that no irreversible treatment should be carried out in TMD (see Occlusal adjustment). Genetic factors TMD does not obviously run in families like a genetic disease. It has been suggested that a genetic predisposition for developing TMD (and chronic pain syndromes generally) could exist. This has been postulated to be explained by variations of the gene which codes for the enzyme catechol-O-methyl transferase (COMT) which may produce 3 different phenotypes with regards pain sensitivity. COMT (together with monoamine oxidase) is involved in breaking down catecholamines (e.g. dopamine, epinephrine, and norepinephrine). The variation of the COMT gene which produces less of this enzyme is associated with a high sensitivity to pain. Females with this variation, are at 2–3 times greater risk of developing TMD than females without this variant. However this theory is controversial since there is conflicting evidence. Hormonal factors Since females are more often affected by TMD than males, the female sex hormone estrogen has been suggested to be involved. The results of one study suggested that the periods of highest pain in TMD can be correlated with rapid periods of change in the circulating estrogen level. Low estrogen was also correlated to higher pain. In the menstrual cycle, estrogen levels fluctuate rapidly during ovulation, and also rapidly increases just before menstruation and rapidly decreases during menstruation. Post-menopausal females who are treated with hormone replacement therapy are more likely to develop TMD, or may experience an exacerbation if they already had TMD. Several possible mechanisms by which estrogen might be involved in TMD symptoms have been proposed. Estrogen may play a role in modulating joint inflammation, nociceptive neurons in the trigeminal nerve, muscle reflexes to pain and μ-opioid receptors. Possible associations TMD has been suggested to be associated with other conditions or factors, with varying degrees of evidence and some more commonly than others. 75% of people with TMD qualify for a fibromyalgia diagnosis and, conversely, 18% of people with fibromyalgia met diagnostic criteria for TMD. A possible link between many of these chronic pain conditions has been hypothesized to be due to shared pathophysiological mechanisms, and they have been collectively termed "central sensitivity syndromes", although other apparent associations cannot be explained in this manner. Recently a plethora