1.1. Epidemiology of gastrointestinal symptoms and endometriosis
It is becoming apparent that, although anatomically separate, gastrointestinal symptoms do overlap with those associated with pelvic endometriosis. Endometriosis is the occurrence of endometrial tissue outside the uterus. Endometriotic deposits are mainly found on the ovaries, utero-sacral ligaments and pelvic peritoneum. Endometriosis affects one-fourth of young women under the age of 30 years with an overall incidence of 7% to 10 % of women. Subfertility occurs in 20-50% of women found to have endometriosis, while more than 80% of women complaining of chronic pelvic pain have this condition. Conversely, endometriosis can be diagnosed in 20-50% of women who are completely asymptomatic, unaware that they have this pelvic pathology .
Gastrointestinal symptoms appear more prevalent in women diagnosed with pelvic endometriosis [2,3,]. Specific signs and symptoms resulting in frequent medical consultation are associated with presence of endometriosis . The anatomical separation between the gastrointestinal tract and the female genital tract may prima facie appear incongruent without any anatomical or physiological association. Gastrointestinal symptoms however such as heartburn and dyspepsia are significantly more commonly found in women with endometriosis compared to controls without pelvic endometriosis [5,6]. These results pose the question as to why two apparently anatomically distant systems, that is the gastrointestinal tract and the female reproductive system, should influence each other [5,6]. Women diagnosed with endometriosis more frequently have concomitant irritable bowel syndrome, often diarrhea predominant . Unlike the upper gastrointestinal tract, the small and especially the large bowel are in close proximity to the female genital tract. Both systems (intestinal and reproductive) are likely to physiologically influence each other [5,6].
Gastrointestinal symptoms commonly occur in the general population. Although estimates vary according to the diagnostic criteria used, 10–40% of the adult population experience heartburn and dyspepsia in Western countries. Gastroesophageal reflux disease increases with age, rising sharply beyond the fourth decade. More than half of the patients affected are aged between 45 and 64 years . Dyspepsia also affects between 20% and 40% of the developed populations. Only a quarter of all cases of dyspepsia can be attributed to gastroduodenal ulcers . Several studies from the 1940’s to the 1980's report that population prevalence of 18%, 26% and 31%  of people referred with dyspepsia have peptic ulcers. Recently this percentage has fallen to around 10–15%. Although mortality in people with gastrointestinal disorders is not raised compared to the general population, these disorders have a significant impact on quality of life. 75% of people with heartburn and dyspepsia suffer persistent symptoms and impaired quality of life over periods of 10 years or more; 30–50% never return to work and are unable to carry out household tasks .
2. Pathogenesis of endometriosis and gastrointestinal symptoms
The enigmatic pathogenesis of endometriosis and its symptoms has led to the formulation of several hypotheses, but none have been proven conclusively. This elusiveness has instigated a search beyond the female genital tract, focussing on the intestine tract that resides in close anatomical proximity to the female genital tract (Figure 1.)[5,6,13]. The overlap of symptoms between both the gut features and endometriosis influences clinical practice and may lead to delayed or misdiagnosis (Figure 1).
Physiological studies indicate that the menstrual cycle normally does not influence gastric motility or emptying; the follicular and luteal phases are not different . Upper abdominal complaints more commonly appear during the follicular phase. During the follicular phase, the transit time through the small intestine is longer. Almost 50% of women with irritable bowel syndrome report a perimenstrual increase in symptoms .
3. Psychological background to the co-existence of endometriosis and gastrointestinal symptoms
Emotional and mood disorders are common and can be marked in women suffering from endometriosis. Many women with endometriosis admit to using regular anxiolytic and/or antidepressant therapy . In one prospective study, 87.5% of 104 women with pelvic endometriosis complained of anxiety, being mild in 24% and severe in 63.5% . There was a strongly positive correlation between pain intensity and anxiety, often requiring anxiolytic treatment with benzodiazepines such as clonazepam. Depression also is prevalent in women with pelvic endometriosis, a high proportion of which require antidepressant therapy. . A similar percentage (86%) of women with chronic pelvic pain are depressed . Work inhibition, dissatisfaction, and sadness are significantly higher rates in those who also have abdominal pain .
Such a psychological profile may have been moulded from a very young age in these women. The cyclical experience from symptoms of severe dysmenorrhoea and menstrual disorders, beginning from puberty, may have conditioned them to acquire certain personality traits as a reaction to the recurring physical and subsequent psychological suffering they sustained . Lower quality of life indices correlates with high pain scores. Lower quality of life status in psychological and environmental perspectives also results in an inverse relationship between pain scores and the psychological dimension of quality of life .
Mood disorders in adult women with endometriosis are associated with co-morbidities such as pain syndromes including irritable bowel syndrome, vulvodynia, fibromyalgia and asthma have been noted with in adult women with endometriosis. These co-morbidities appear to have their inception early in reproductive life. In one study involving 138 adolescents/young women (younger than 24 years), 56% experienced comorbid pain syndromes, 48% had mood conditions, and 26% asthma .
Exacerbations of gastrointestinal motility disorders such as gastroesophageal reflux and irritable bowel syndrome are associated with the emergence of psychosocial stressors. Naliboff et al  assessed 60 subjects with current heartburn symptoms and correlated for the occurrence of stressful life events retrospectively over the preceding 6 months and prospectively for 4 months. The occurrence of a severe, sustained life stress during the previous 6 months significantly predicted increased heartburn symptoms during the following 4 months. Anxiety showed the strongest correlation to impaired quality of life and depression to heartburn medication use. Similar to other chronic conditions such as irritable bowel syndrome, heartburn severity appears to be most responsive to major life events. Both heartburn and irritable bowel syndrome may be related to gastrointestinal motility disorders . In the upper gastrointestinal tract esophageal acid exposure due to inhibition of gastric emptying of acid may lead to heartburn. Alternatively, motility disorders affecting the lower intestinal tract can contribute to the irritable bowel syndrome.
On further investigation of gynaecological complaints, once the diagnosis of endometriosis is established, the phobia of infertility may set in, further compounding the psychological profile. If infertility does occur in these women, then depressive symptoms are more likely to appear. Self-reported depression is more common in subfertile women with endometriosis compared to fertile women .
4. Neuroendocrine imbalance in association with gastrointestinal symptoms and endometriosis
The majority of women suffering from endometriosis are well versed in their condition. With easy access to medical literature, besides subfertility, they become aware of the risk of inflammatory bowel disease and ovarian cancer . All these factors exacerbate the tenuous emotional status of these women (Figure 2.).
In response to high levels of perceived stress, neuroendocrine-immune imbalance represents a further influence on the symptoms of endometriosis. Serum prolactin and cortisol levels are significantly higher in infertile women with stage III-IV endometriosis . Perception of stress is known to trigger or intensify the incidence or exacerbation of diseases such as inflammatory bowel disease, immunological cutaneous conditions, or pregnancy complications such as spontaneous miscarriage and pre-eclampsia. Chronic stress alters the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. As both systems can modulate intestinal mucosal immune function, this impact of stress is a potential mechanism leading to the irritable bowel syndrome. In those with the irritable bowel syndrome, this is reflected by diminished basal adrenocorticotropin hormone levels and high basal and stimulated plasma cortisol levels . There may also be an inflammatory component: as mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] is decreased in the sigmoid colon from patients with diarrhea-predominant irritable bowel syndrome .
The association between psychological status and the gastrointestinal tract has been well-established from the pioneering work of Beaumont . In a subject with a traumatically exposed gastric fistula, an angry state resulted in instant reddening of the mucosa, connecting the neuroendocrine-emotional status with gastric physiology. Heartburn and dyspepsia are acknowledged symptoms related with psychological and mood disorders. Gastroesophageal reflux disease can be anatomically related to dysfunction of the gastroesophageal junction, even though psychological factors play an important role in exacerbating symptoms. Well-defined personality factors modulate the effect of stress on the lower esophageal sphincter, just as they can influence the perception and assessment of symptoms. Gastroduodenal motor disorders and gastric acid hypersecretion interact with psychological and neurohormonal factors, culminating in dyspepsia being experienced. Greater proximal extension of acid during reflux episodes occurs in patients with proven gastroesophageal reflux disease. These patients describe a shorter history of symptom onset and worse anxiety scores. Meanwhile, endoscopy depicts gastritis .
Altered gastric acid secretion has been linked to a vast array of modulators supporting the neuro-endocrinological connection. Central neurotransmitters and/or neuromodulators may excite or inhibit gastric acid secretion, particularly excitatory neuroendocrine modulators such as gamma-aminobutyric acid (GABA), acetylcholine, thyrotropin releasing hormone, and oxytocin. Conversely, noradrenaline, adenosine, bombesin, calcitonin-gene related peptide, corticotropin releasing factor, beta-endorphin, neurotensin, neuropeptide Y, insulin-like growth factor II and prostaglandins inhibit gastric acid secretion.
Several of these neuroendocrine mediators are pertinent in the setting of endometriosis. Deep infiltrating endometriosis is associated with severe and frequent chronic pelvic pain. In these cases significantly more nerve fibres are detected histologically than in superficial peritoneal endometriotic lesions. Deep infiltrating endometriotic lesions are abundantly innervated by sensory nerve fibres that use acetylcholine and norepinephrine as neurotransmitters . Women with endometriosis have lower serum progesterone levels during the follicular phase; progesterone levels are inversely correlated to pain scores. Progesterone receptor-positive peritoneal lymphocytes [CD56(+) and CD8(+)] increase in advanced endometriosis. Cytokine secretion by peritoneal cells is higher in cells derived from endometriosis patients and can be further heightened by corticotrophin releasing hormone-mediated inflammation. Peripheral corticotrophin releasing hormone increases with anxiety and emotional stress, and so might contribute to the peritoneal inflammation present in endometriosis [28,29].
5. Gastrointestinal symptoms, the menstrual cycle and endometriosis
An increase in the prevalence of gastrointestinal symptoms transpires around the time of menses and early menopause . These are periods in the reproductive cycle punctuated by a decline or low level of ovarian hormones. Hence, estrogen and progesterone withdrawal may contribute either directly or indirectly to the development of gastrointestinal symptoms . In women with endometriosis, the situation is complex. Due to significant overlap between the symptoms of endometriosis and those related to endometriotic deposits on the gastrointestinal system, endometriosis has been referred to as the “great masquerade”. Moreover, the menstrual cycle may also impact gastrointestinal function.
Abdominal symptoms are significantly more pronounced at the beginning of the menstrual cycle in the follicular phase . Around 30% of otherwise asymptomatic women may experience gastrointestinal symptoms at the time of menstruation, and almost fifty percent of women with irritable bowel syndrome complain of a perimenstrual increase in symptoms. Nausea, epigastric pain, and loose stools diarrhoea are more prevalent at the time of menses in women complaining of bowel dysfunction. Patients with bowel motility-type symptoms experience their high abdominal pain throughout the menstrual cycle. Those with endometriosis complain that cramping pain occurs more frequently in the perimenstrual phase .
Intestinal motility disorders may be associated with the genesis of endometriosis while conversely endometriosis may influence intestinal motility. There is significantly more colonic damage, myeloperoxidase activity, and leucocyte count numbers compared to controls. Increased tension in the longitudinal muscle correlates with leukocytosis and colonic damage. In deep infiltrating endometriosis, internal anal sphincter tone is increased and incomplete evacuation is a common symptom .
Diet can affect premenstrual symptoms. The ingestion of total saturated and monounsaturated fats adversely changes objective scores for premenstrual symptoms and pain . Soy products have no effect whereas the consumption of cereals/potatoes/starches had an inverse effect on such a distress scores during the premenstrual phase .
Presumably due to hormonal and menstrual differences, twice as many women as men seek health services for irritable bowel syndrome. The presence of dyspepsia in women is a significant independent risk factor for new-onset irritable bowel syndrome. The majority of women with irritable bowel syndrome requesting medical consultation are of reproductive age experiencing the hormonal fluctuations of the menstrual cycle. However, after the age of 50 most population surveys have reported a decline in the prevalence of irritable bowel syndrome . Both estrogen and progesterone influence 5-hydroxytryptamine, an amine which is known to effect intestinal motor-sensory function. When estrogen and progesterone levels reach their lowest levels in the menstrual cycle, the platelet-depleted plasma concentration of 5-hydroxytryptamine in irritable bowel syndrome patients with diarrhea are similar to that in healthy controls . Compared to males, females with irritable bowel syndrome more commonly display non-painful gastrointestinal symptoms, constipation and somatic discomfort. There appear to be different gender-related pathways in the sympathetic nervous system response to rectosigmoid stimulation, perhaps a factor in eliciting visceral hypersensitivity that represents a major factor in functional gastrointestinal diseases. Women with irritable bowel syndrome have significantly lower rectal discomfort thresholds in response to barostat-assisted distensions of the rectosigmoid colon, when compared to men with irritable bowel syndrome and to healthy women who are the least sensitive.  Women in general and those with the irritable bowel syndrome may experience a lower discomfort threshold after noxious stimulation compared to men. Men with irritable bowel syndrome may not experience such a difference in the threshold for rectal discomfort compared to asymptomatic male controls.
Oral contraception results in a relatively strict regulation of the menstrual cycle. Moreover the use of oral contraception is associated with reduced menstrual loss and diminished levels of dysmenorrhoea. During menstruation, women with irritable bowel syndrome using oral contraceptives experience significantly less cognitive, anxiety, and depression symptoms but no differences for most symptoms of irritable bowel syndrome . There may be a differential effect of oral contraception depending on the gastrointestinal symptom pattern. There is clearly a sex-based difference in experiencing abdominal pain .
The presentation of endometriosis may mimic that of inflammatory bowel disease. The cramping pain of dysmenorrhea is due to contraction of uterine smooth muscle under the influence of prostaglandins, released by the endometrium during menstruation. The inflammatory process in active inflammatory bowel disease is, in part, also related to prostaglandin levels. Elevated prostaglandin levels increase contractility of intestinal smooth muscle resulting in diarrhea, intestinal secretion and abdominal pain. It is critically import to distinction clinically between endometriosis and inflammatory bowel disease. Non-steroidal anti-inflammatory drugs are administered to relieve the symptoms of dysmenorrhea in the presence and absence of endometriosis. However, non-steroidal anti-inflammatory agents can exacerbate inflammatory bowel disease and hence, generally contraindicated.
5.1. Dietary components in relation to symptomatic endometriosis and gastrointestinal symptoms
The injudicious ingestion of dietary components, an accompaniment of psychological stress, may aggravate gut symptoms. Somatization, anxiety and binge eating are significant predictors of coexistent gastrointestinal disorders. The body mass index of women who experience depression is significantly higher than controls such that depressive states and obesity have a reciprocal relation. As obesity has an important role in digestive symptoms, particularly those related to gastroesophageal reflux, this becomes an important consideration in management. Indeed, dietary modification may even be useful in treating mood disorder by providing a more favourable risk-benefit ratio than contemporary psychotropic agents . Micronutrients and other dietary components are certainly important underpinnings for general physical and mental health.
5.2. Pharmacological treatment of endometriosis and gastrointestinal symptoms
Anxiety states lead to the excessive ingestion of drugs that relax the lower esophageal sphincter and so facilitate gastroesophageal reflux. Depression treated with clomipramine, for example, is associated with an increased risk of esophageal reflux . Moreover, depression and its therapy are predictive of developing obesity. Early during the first 6 weeks of nortriptyline treatment, weight gain commences, reaching on average 1.2 kg at 12 weeks with a resultant 0.44% increase in body mass index .
The chronic intake of non-steroidal anti-inflammatory agents to counter endometriosis-induced dysmenorrhoea and menorrhagia can lead to gastroduodenal mucosal damage. The degree of non-steroidal anti-inflammatory gastropathy may be severe enough to develop gastric and duodenal ulceration. This can be avoided if medical practitioners were persuaded to change their prescribing practices .
Gastrointestinal symptoms and endometriosis often co-exist, both causing particularly abdominal pain. Their linkage shares a common psychological background and neuroendocrine mediation. Gastrointestinal symptoms often relate to both dietary indiscretion and psychological stress, both of which may be commonly encountered in women with endometriosis for a variety of reasons. Moreover treatment of the symptoms of endometriosis may aggravate gastrointestinal symptoms.
In suspected endometriosis, meticulous consultation carefully assessing the woman’s symptomatology is required to avoid delay or possibly misdiagnosis. Confounding the diagnosis and management likely will exacerbate the psychopathology of anxiety and depression, while aggravating the gastrointestinal symptoms. The co-existence of gastrointestinal conditions and endometriosis may require a multi-disciplinary approach to enact effective treatment.