It's not surprising that many gastrointestinal diseases have been associated with dyspepsia. However, many non-gastrointestinal diseases also have been associated with dyspepsia. Examples of the latter include diabetes, thyroid disease, hyperparathyroidism (overactive parathyroid glands), and severe kidney disease. It is not clear, however, how these non-gastrointestinal diseases might cause dyspepsia. A second important cause of dyspepsia is drugs. It turns out that many drugs are frequently associated with dyspepsia, for example, nonsteroidal anti-inflammatory drugs [(NSAIDs, such as ibuprofen), antibiotics, and estrogens]. In fact, most drugs are reported to cause dyspepsia in at least some patients.

Most dyspepsia (not due to non-gastrointestinal diseases or drugs) is believed to be due to abnormal function (dysfunction) of the muscles of the organs of the gastrointestinal tract or the nerves controlling the organs. The nervous control of the gastrointestinal tract, however, is complex. A system of nerves runs the entire length of the gastrointestinal tract from the esophagus to the anus in the muscular walls of the organs. These nerves communicate with other nerves that travel to and from the spinal cord. Nerves within the spinal cord, in turn, travel to and from the brain. (The gastrointestinal tract is exceeded in the numbers of nerves it contains only by the spinal cord and brain.) Thus, abnormal function of the nervous system in dyspepsia might occur in a gastrointestinal muscular organ, the spinal cord, or the brain.

As already mentioned, abnormal function of the nerves of the gastrointestinal organs, at least theoretically, might occur in the organ, spinal cord, or brain. Moreover, the abnormalities might occur in the sensory nerves, the motor nerves, or at processing centers in the intestine, spinal cord, or brain.

Another potential cause of dyspepsia is bacterial overgrowth of the small intestine (small intestinal bacterial overgrowth), although the frequency with which this condition causes dyspepsia has not been determined, and there is little research in the area. The relationship between overgrowth and dyspepsia needs to be pursued, however, since many of the symptoms of dyspepsia are also symptoms of bacterial overgrowth. Overgrowth can be diagnosed by hydrogen breath testing and is treated primarily with antibiotics.

Other diseases and conditions can aggravate functional diseases, including dyspepsia. Anxiety and/or depression are probably the most commonly recognized exacerbating factors for patients with functional diseases. Another aggravating factor is the menstrual cycle. During their periods, women often note that their functional symptoms are worse. This corresponds to the time during which the female hormones, estrogen and progesterone, are at their highest levels. Furthermore, it has been observed that treating women who have dyspepsia with leuprolide (Lupron), an injectable drug that shuts off the body's production of estrogen and progesterone, is effective at reducing symptoms of dyspepsia in premenopausal women. These observations support a role for hormones in the intensification of functional symptoms.

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