Researchers and medical experts are not sure of the exact causes of POTS. However, they have identified some links between the symptoms and other conditions, as well as certain risk factors. Notably, females are between four and five times more likely to develop POTS than males. It also tends to develop in people who have recently experienced acute stressors such as pregnancy, surgery, or trauma. POTS has links to diseases such as diabetes, irritable bowel syndrome, anemia, and autoimmune diseases. Secondary POTS often occurs alongside Ehlers-Danlos syndrome (EDS), a hereditary tissue disorder that features extremely flexible joints, elastic skin, and easy bruising.

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