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Chronic Constipation: Etiology and Pathophysiology

  • Authors: Brian E. Lacy, MD, PhD
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Target Audience and Goal Statement

This activity is intended for gastroenterologists, primary care physicians, pharmacists, nurse practitioners, and physician assistants.

The goal of this activity is to provide foundational as well as advanced education on the pathophysiology and treatment targets, evaluation of patients, and expert guidance on the available and emerging therapies.

Upon completion of this activity, participants will be able to:

  1. Identify patients with chronic constipation who do not adequately respond to laxatives
  2. Evaluate the pathophysiology and etiology of chronic constipation and targets for available and evolving chronic constipation therapies


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  • Julia Muino

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    Clinical Editor, Medscape, LLC


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  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


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Chronic Constipation: Etiology and Pathophysiology


Progesterone Receptors

Several lines of evidence support the theory that sex hormones, particularly progesterone, play a role in the development of constipation. It is well known that constipation is more prevalent in women than men and more problematic during pregnancy. Additionally, colonic transit time is longer during the luteal phase than in the follicular phase of the menstrual cycle.[33]

In a study of women with STC, the progesterone receptor was over-expressed and progesterone was found to reduce the effects of ACh and 5-HT on muscle cells in vitro.[34] Therefore, progesterone and an over-abundance of progesterone receptors may partially inhibit excitatory neurotransmitters from functioning normally. Although preliminary, these findings may explain why women are more prone to constipation and more susceptible to constipation during certain phases of the menstrual cycle.


The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) plays a major role in gastrointestinal tract motor function. Approximately 95% of the body's 5-HT resides within the gastrointestinal tract. Distention of the gut lumen triggers enterochromaffin cells to release 5-HT. In turn, 5-HT stimulates the local release of ACh and NO, causing muscle contraction upstream and muscle relaxation downstream, respectively. Although human data are limited, slow transit constipation may be related to both a deficiency in 5-HT production and 5-HT release, and a reduced expression of 5-HT receptors in the circular muscle layers of the colon.[35,36] The stimulatory effects on the colon of 5-HT agonists, such as tegaserod and prucalopride, support this view.[37-40]

Substance P

Substance P is a neuropeptide within the family of tachykinins. It is present in excitatory motor neurons, interneurons and sensory neurons. It is generally thought to have an excitatory mode of action and appears to be an important factor in normal colonic peristalsis. Two recently published studies reported that levels of substance P nerve fiber density were lower in children with slow transit constipation compared with children without slow transit constipation.[40,41] Reduced levels of this excitatory neurotransmitter may contribute to constipation in some patients.

Nitric Oxide

NO is one of the major inhibitory neurotransmitters in the gastrointestinal tract. NO plays a critical role in gut peristalsis when produced and released in normal amounts. Excess production of NO may inhibit colonic motility in some patients with slow transit constipation.[42] Additional studies are needed to confirm the role of NO in constipation.

Chloride Secretion

Chloride is the predominant electrolyte-driving fluid secretion into the colon. Abnormalities of chloride secretion can cause a secretory diarrhea due to an excess of chloride ion secretion, or constipation, due to a deficiency of chloride secretion (eg, cystic fibrosis). Although chloride channel activators seem to be quite effective at treating symptoms of constipation, there is a paucity of data on the role of chloride secretion in constipation. A recent study compared chloride secretion from colonic epithelial cells in children with functional constipation with controls. Basal chloride secretory rates were similar, but calcium-linked stimulation was reduced among those with functional constipation.[43] Although the precise location of this deficiency was not identified -- such as at the receptor or chloride channel level -- these results lend support for use of chloride activating agents for treatment of constipation.

Colonic Motor Dysfunction

There are data on the characterization of motor patterns in patients with slow transit constipation. Some patients with slow transit constipation have a reduced number of HAPCs.[44,45] Others have a reduced number of ICCs[20, 46] or abnormalities of the myenteric plexus or nerve fibers in the colon.[47,48] As previously noted, some may have abnormalities in specific neurochemical classes of myenteric neurons, including ACh, SP, 5-HT or NO.[18,19,41,42] Thus it appears that, even within the subcategory of slow transit constipation, there is a variety of pathophysiologic processes can produce symptoms of constipation.


Constipation is a highly prevalent disorder that significantly affects quality of life. Patients describe a variety of symptoms when asked about constipation; these symptoms are not limited to stool frequency. The pathophysiology of constipation is diverse. Emerging data on receptors, chloride channels, neurotransmitters, and hormones will enable better understanding of this complicated disorder and will lead eventually to better treatments.

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