by Brooke Lee Keefer
Sphincter of Oddi Dysfunction (SOD) is an elusive, difficult to diagnose disease that is even more difficult to treat. One reason for this is we don’t know what causes SOD. Undoubtedly, if we knew the cause of SOD, we could begin research trials to effectively treat it. One possible cause of SOD is hormones, since research studies estimate 75 to 90% of SOD sufferers are women. It makes sense SOD research would focus on hormones, right? Wrong. Though it is a female-dominant disease, research is sparse linking hormones to SOD.
Hormonal Differences in Men and Women
My SOD came to be after a cholecystectomy (gallbladder removal) a few years after having my second son. My SOD symptoms went nearly dormant during the pregnancy of my third son, a time when my female reproductive hormone levels surged. The symptoms returned with a vengeance after his birth, when the same hormones plummeted. The same is true for many women I know with SOD.
The primary hormone difference between men and women are the reproductive hormones, estrogens and androgens (ex. testosterone). Estrogens have a profound effect on the gastrointestinal system, androgens not so much. Variations in these hormones not only effect the male and female reproductive system, but also the digestive system and digestive hormones. Men and women have the same hormones, yet there is some important variation in hormone levels and patterns, and there are some differences in how the hormones interact with male and female bodies. (1)
Estrogen and Progesterone
While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. The three major naturally occurring estrogens in women are estrone (E1), estradiol (E2), and estriol (E3). (2) Probably the most obvious effect women’s hormones have on the digestive system is estradiol’s effect on the gallbladder. Women are twice as likely as men to have gallstones because estradiol raises cholesterol levels in the bile and slows gallbladder movement. (3) One study on prairie dogs showed that Sphincter of Oddi motility was significantly reduced during estrogen infusion, primarily due to decreased phasic wave frequency. (4) This meant that estrogen relaxed the sphincter.
Progesterone is another predominantly female hormone. The imbalances of estradiol and progesterone can influence the movement of food through the intestines—some by speeding the process up, causing diarrhea, nausea and abdominal pain; and others by slowing things down and causing bloating and constipation. (5) In pregnancy, an increase in the hormone progesterone contributes to constipation by slowing the waves of muscle contractions that move food down the digestive tract. (6) In addition, progesterone causes the stomach's esophageal valve to relax, causing Gastroesophageal reflux disease (GERD). Since progesterone has a relaxation effect, maybe this is a reason SOD improves for most women during pregnancy, when progesterone levels are high. Progesterone also alters partitioning of hepatic bile between gallbladder and small intestine and, therefore, gallbladder filling. (7) What is especially interesting with the estrogen-gallbladder connection is most SOD sufferers report the onset of symptoms appeared post-cholecystectomy.
There are also several key hormones specific to the gastrointestinal system that could play a role in SOD. Although there are no glaring gender differences with these hormones, estrogen and progesterone affect some if not all. Therefore, the male/female difference is alive and well with these hormones as well. The most common of these are cholecystokinin (CCK), secretin, and gastrin.
Cholecystokinin (CCK) is a peptide hormone that plays a key role in digestion and could very well be the key to unlocking the mysterious cause of SOD. CCK’s role with the Sphincter of Oddi (SO) is interesting. Ingestion of a fatty meal is followed by release of cholecystokinin (CCK) which causes the gall bladder to contract and the SO to relax. Coordination of gall bladder and SO function may also be influenced by nerve bundles which connect the gall bladder and SO via the cystic duct. Cholecystectomy may influence normal SO function by disrupting this nerve pathway and altering its response to CCK. (8)
CCK is released into the bloodstream after eating a meal by endocrine cells located in the small intestine. Depending on which cells are receiving the CCK signal, the result can be either that digestive enzymes are delivered into the intestine from the pancreas, the gallbladder empties bile and food is shuttled faster through the intestine, or the person stops eating because they feel full. (9) Cholecystokinin is also produced by neurons in the enteric nervous system, and is widely and abundantly distributed in the brain. Studies also link CCK to panic attacks. (10) This is interesting as most SOD sufferers report stress triggers their symptoms.
There really is no difference with CCK among men and women outside of the effect estrogen and progesterone have on it. Progesterone significantly affects gallbladder emptying in response to CCK by inducing a concentration-dependent relaxation of the gallbladder. (11) In addition, it is well documented that estradiol regulates CCK and induces a relaxation of CCK-induced tension. When I had a Hida scan the doctor gave me CCK and can say my SOD pain flared immediately following the injection.
Other digestive hormones requiring attention are secretin and gastrin. Secretin functions as a type of fireman: it is released in response to acid in the small intestine, and stimulates the pancreas and bile ducts to release a flood of bicarbonate base, which neutralizes the acid. (12) All of this transiently increases the tone of the SO. Gastrin may play a role in SOD. Most who suffer from SOD symptoms following cholecystectomy have higher serum levels of gastrin, likely caused by sphincter of Oddi hypomotility and duodenal-biliary reflux. (13) I could not find research studies on estrogen or progesterone affecting secretin or gastrin. That is not to say they don’t have an effect. There just isn’t any research on it. The same goes for pituitary and adrenal hormones which could have an effect on the SO.
Though I have pointed out the hormonal differences in men and women and how female reproductive and other hormones affect the SO, it is still unclear why some women are asymptomatic when their hormone levels are high (during pregnancy) and symptomatic when hormone levels plummet. Since men have a low level of these same hormones then wouldn’t they equally suffer from SOD? Possibly, it is the fluctuations themselves that make women more vulnerable and not the actual hormone level. In other words, the SO likes a steady level of hormones throughout its lifespan. Women’s hormone levels are far from consistent. We deal with variations every month throughout our cycle, pregnancy surges, the erratic fluctuations of perimenopause, and the near death of our hormones from menopause. Further, the sudden absence of a gallbladder may tip the scales over beyond what the SO can handle. It certainly is a mystery that needs solving. We desperately need researchers to focus on this unchartered territory!
1. Fuentes, Agustin. “Men and Women Are the Same Species!”. Psychology Today. May 24, 2012. https://www.psychologytoday.com/blog/busting-myths-about-human-nature/201205/men-and-women-are-the-same-species.
2. Wikipedia: Estrogen. https://en.wikipedia.org/wiki/Estrogen
3. Stinton, L. and Shaffer, E. “Epidemiology of Gallbladder Disease: Cholelithiasis and Cancer”. Gut Liver. 2012 Apr; 6(2): 172–187.
4. Tierney, S., et al. “Estrogen inhibits sphincter of Oddi motility”. The Journal of Surgical Research. 1994 Jul;57(1):69-73.
5. “Digesting It All!” Connections: An Educational Resource for Women’s International Pharmacy. https://www.womensinternational.com/connections/digesting.html.
6. Lingen, J. “The Second Trimester: Constipation, Gas, & Heartburn”. Healthline. March 5, 2012. http://www.healthline.com/health/pregnancy/second-trimester-constipation-gas-heartburn.
7. Tierney, S., et al. “Progesterone alters biliary flow dynamics”. Annals of Surgery. 1999 Feb; 229(2): 205–209.
8. Luman, W., et al. “Influence of Cholecystectomy on Sphincter of Oddi Motility”. Gut. 1997;41:371-374 doi:10.1136/gut.41.3.371. http://gut.bmj.com/content/41/3/371.long.
9. “Hormones, the Pancreas, and Obesity”. Discrovery’s Edge (Mayo Clinic Magazine). November 2010. http://www.mayo.edu/research/discoverys-edge/hormones-pancreas-obesity.
10. “Cholecystokinin”. Pathophysiology of the Digestive System. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/gi/cck.html.
11. Kline, et al. “Progesterone inhibits gallbladder motility through multiple signaling pathways”. Steroids. 2005 Aug;70(9):673-9. http://www.ncbi.nlm.nih.gov/pubmed/15916787.
12. “Secretin”. Pathophysiology of the Digestive System. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/gi/secretin.html
13. Zhang, ZH, et al. “Sphincter of Oddi hypomotility and its relationship with duodenal-biliary reflux, plasma motilin and serum gastrin”. World Journal of Gastroenterology. 2008 Jul 7;14(25):4077-81. http://www.ncbi.nlm.nih.gov/pubmed/18609694