Introduction
Numerous studies exist highlighting the impact of hormonal changes during pregnancy on various gastrointestinal conditions, including improvement in irritable bowel syndrome (IBS) and aggravations in constipation. Epidemiologically there is a variation in digestive concerns between men and women, with higher rates of IBS, inflammatory bowel disease (IBD), gallstones affecting women and higher rates of gastric ulcer and gastric cancers occurring in men.
The sex hormones discussed in this narrative include testosterone, estrogen and progesterone. Estrogen and progesterone are secreted predominantly from the ovaries, though recent studies report local production and effect of estrogen in other areas of the body, far removed from the reproductive system. Estradiol receptor β (ERβ) is found in enteric nerve cells as well as colonic smooth muscle cells suggesting estradiol, the more potent type of estrogen, may regulate intestinal motility. ERβ is linked to Na+/H+ exchanger protein in membranes of cells of the proximal colon; where 17β-estradiol (E2) stimulates its upregulation resulting in changes in water balance, potentially influencing the consistency of stool. Progesterone may also indirectly contribute to intestinal motility regulation through cytokine and prostaglandin release. The impact of testosterone, produced in Leydig cells of the testes, on intestinal motility is less known (Wang 2009).
This narrative will explore the impact that sex hormones have on several gastrointestinal conditions as well as examine the physiological processes underlying these connections, including impact on the gut immune system, microbiota and digestive hormone secretion.
Gastric Ulcers
Gastric ulcers are sores or openings in the inner lining of the stomach which typically produce symptoms of epigastric pain, nausea, frequent bouts of hunger and possible weight loss. Ulcers are more prevalent in men than women, and according to an animal study by Machowaska et al (2004) may be aggravated by testosterone. The administration of testosterone significantly reduced blood flow to the ulcerated area, prevented gastrin release (a peptide with protective and healing properties), and increased the release of a pro-inflammatory cytokine, interleukin 1-β. In the study conducted by Drago (1999) removal of testosterone, by way of testectomy, improved healing time of gastric ulcres. Interestingly, the administration of progesterone had the same effects. Manipulating estrogen did not yield clear results as E2 was reported to have pro-ulcerogenic effects in one study (Drago 1999) and protective effects in another (Smith 2008).
Inflammatory Bowel Disease (IBD)
IBD is a chronic inflammatory condition that involves various parts of the gastrointestinal tract and produces symptoms of bloody diarrhea, abdominal pain, reduced appetite and low grade fever. Ulcerative colitis (UC) and Crohn’s disease are examples of this condition and are more prevalent in women than men. Dehydroepiandrosterone (DHEA), a precursor to several sex hormones, has been shown to be reduced in patients with IBD. This may contribute to the pathogenesis as DHEA has direct anti-inflammatory properties. What leads to low DHEA levels and whether its reduction leads to alternations in testosterone and E2, its downstream metabolites, is unclear. The administration of DHEA appears to offer protection as demonstrated in a pilot study by Andus et al (2003). Twenty participants with UC and Crohn’s were supplemented with 200mg DHEA once/day for 56 days. Supplementation resulted in clinically significant improvement in both groups with 6 of 7 patients with Crohn’s and 6 of 13 patients with UC achieving remission and a decrease in blood diarrhea, abdominal pain and liquid stools. No masculinization effects were observed.
Irritable Bowel Syndrome (IBS)
IBS is defined as a sensory-motor disorder of the digestive tract with symptoms of abdominal pain and alternating bowel habits, ranging from constipation to diarrhea. Prevalence of IBS varies between 3:1 and 5:1 depending on the clinical setting, with higher rates in female patients (Mulak 2014). The hormonal influence is evident as symptoms of IBS change throughout the menstrual cycle and respond to oral contraceptive and hormone replacement therapies. Their mechanism of influence is believed to be through changes in gastrointestinal transit time, visceral hypersensitivity and gut permeability. Estrogen has an inhibitory effect on colonic contractility resulting in slower transit time, while progesterone appears to have dual function, with high dose reducing motility and low dose administration increasing motility. Fluctuations of progesterone throughout the menstrual cycle could play a role in the alternating constipation and diarrhea symptoms seen with IBS. Animal studies examining abdominal pain sensitivity report similar dual impact from estradiol with standard dose causing hypersensitivity and high dose resulting in anti-nociception.
Maintenance of an intact intestinal barrier is important in water balance, immune defense, healthy absorption and other digestive functions. A decrease in intestinal permeability has been reported with estradiol supplementation, as well as BPA and soy exposure, suggesting a protective role of estrogen in gut barrier maintenance (Meleine 2014). While there are several plausible physiological explanations for the hormonal impact on IBS, the exact mechanism remains to be defined.
Gallbladder Disease
Gallstones, in particular stones predominantly made of cholesterol, occur twice as frequently in women than men and are believed to be promoted by estrogen. Oral contraceptives and conjugated estrogen hormone replacement therapy both result in increased cholesterol gallstone formation, with similar impact demonstrated in men receiving estrogen for prostatic cancer therapy (Wang 2009). E2 promotes lithiasis (stone formation) by upregulating the expression of ESR1 in the liver. This results in increased secretion of cholesterol and supersaturation of bile. Conversely, progesterone has been demonstrated to reduce gallbladder emptying time resulting in stasis, which can further promote lithiasis (Tierney 1999). It is interesting that soy, a phytoestrogen, has been demonstrated to reduce the cholesterol content of gallstones (Tomotake 2000), though its effect may be independent of its estrogenic-like activity.
Colon Polyps
Colon polyps are produced from a local overgrowth of colonic cells and are typically asymptomatic. The frequency of colonic polyps, also known as adenomas, is higher in men and their onset is earlier. Amos-Landgraf et al (2014) examined the role of testosterone and estrogen on the formation of adenomas in an animal study. The removal of estrogen, by ovariectomy, did not impact the formation frequency in female rats, while orchiectomy yielded a significantly protective effect on adenomas, which was reversed with testosterone supplementation. As there were no androgen receptors found in the tumors, testosterone is thought to have indirect impact on adenomagenesis. This impact may occur through the modification of gut microbiota, which has been demonstrated to be different between men and women and responsive to hormonal changes (Yurkovetrskiy 2013).
Colorectal Cancer (CRC)
Estrogen has been linked to not only reproductive cancers, such as breast and uterine, but also non-reproductive cancers like colorectal cancer. The connection between hormones and CRC has been supported by the Women’s Health Initiative observation study that demonstrated a 30% reduction in CRC incidence in post-menopausal women receiving hormone replacement therapy (HRT) (Caizza 2015). The protective mechanism of HRT appears to be dependent on the estrogen-receptor β (ERβ). Studies examining animals without the ERβ (genetic knock-outs) demonstrate increased hyperproliferation of colonic cells, loss of differentiation and reduced apoptosis, all of which predispose to carcinogenesis. Clinically, ERβ can be present in both healthy and cancerous cells, with advanced cancer cells demonstrating a reduction and/or complete loss of ERβ. Additionally, the lack of ERβ within cancer cells (ERβ negative status) is associated with a poorer prognosis.
Xenoestrogens, which are endocrine disruptors with estrogen-like effects, have been implicated in colon carcinogenesis. Bisphenol A (BPA) has been demonstrated to have anti-estradiol activity preventing the apoptosis of colon cancer cells in an in vitro study (Marino 2014). On a positive note, flavonoids that act on the ERβ, such as quercetin and naringenin have been shown to have an anti-colon cancer effect, also demonstrated in vitro (Marino 2014).
Conclusion
While the full extent of the role that sex hormones play in gastrointestinal health remains to be further explored, their possible contribution to gastrointestinal pathology presents a new target for therapeutic interventions. Clinically exploring the connection between sex hormones and gastrointestinal health in patient care may yield additional therapeutic approaches and interventions that may not have been considered otherwise.
References
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