**5. Neuro-endocrine 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, the risk of inflammatory bowel disease and ovarian cancer has now become universally known to most women suffering from endometriosis [21]. All these factors exacerbate the tenuous emotional status of these women (Figure 2.)

In response to high levels of perceived stress, neuroendocrine-immune imbalance has been alluded to as a reaction to the symptoms of endometriosis. Serum prolactin levels were significantly higher in infertile women with stage III-IV endometriosis (28.9 +/- 2.1 ng/mL) than in healthy controls (13.2 +/- 2.1 ng/mL)[22]. Elevated serum cortisol levels were noted in infertile women with stage III-IV endometriosis (20.1 +/- 1.3 ng/mL) compared to controls (10.5 +/- 1.4 ng/mL) [22]. Perception of stress has been noted 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. The effect on the immunity of the intestinal mucosa by stress has been implicated as a potential mechanism leading to irritable bowel syndrome. This is thought to be mediated through altered function of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. A study by Chang et al indicated that basal adrenocorticotropin hormone levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients with irritable bowel syndrome. Patients with irritable bowel syndrome presenting with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon versus controls (P < 0.05) [24].

Factors influencing Gastric Acid Secretion

oxytocin have been cited. On the contrary, noradrenaline, adenosine, bombesin, calcitoningene related peptide, corticotropin releasing factor, beta-endorphin, neurotensin, neuropep‐ tide Y, insulin-like growth factor II and prostaglandins have been shown to inhibit gastric acid

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175

Several of these neuro-endocrine mediators have also been noted in 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 were shown to be innervated abundantly by sensory nerve fibres utilizing acetylcholine and norepinephrine as neurotrans‐ mitters [27]. Women with endometriosis have been noted to have lower levels of progesterone in serum in the follicular phase and progesterone levels were inversely correlated to pain scores. Progesterone receptor positive peritoneal lymphocytes of CD56(+) and CD8(+) type were increasing found in advanced endometriosis. Cytokine secretion by peritoneal cells, was higher in cells derived from endometriosis patients and could be further heightened by corticotrophin releasing hormone mediated inflammation. Peripheral corticotrophin releasing hormone increasing with anxiety and emotional stress, might contribute to the peritoneal

**6. Gastrointestinal symptoms, the menstrual cycle and endometriosis**

to the occurrence of gastrointestinal symptoms and possibly to pathology [30].

An increase in the prevalence of gastro-intestimal symptoms are noted around the time of menses and early menopause [30]. These are periods in the reproductive cycle whereby a significant decline or low level of ovarian hormones in serum are noted. These observations suggest that estrogen and progesterone withdrawal may contribute either directly or indirectly

Due to significant overlap between the symptoms of endometriosis and symptoms related to endometriotic deposits on the gastrointestinal system, endometriosis has been referred to the great masquerader. Moreover the menstrual cycle may also impact on gastrointestinal function. As confirmed in the general literature, the presence of frequent menstruation in our study in patients with endometriosis increased the likelihood of related gastrointestinal

Abdominal symptoms are significantly more pronounced at the beginning of the menstrual cycle in the follicular phase [14]. 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 complaining of bowel motility symp‐ toms indicate that stomach pain was higher throughout the menstrual cycle. Patients with endometriosis complained of cramping pain more commonly in the perimenstrual phase [31]. Intestinal motility disorders may be associated with the genesis of endometriosis and con‐ versely endometriosis may influence intestinal motility. Preclinical studies have shown

secretion.

symptoms.

inflammation present in endometriosis [28,29].

secretion of gastric acid. This compounded by dietary indiscretion and injudicious ingestion of nonsteroidal inflammatory **Figure 2.** The secretion of central neurotransmitters and hormones such as cortisol and prolactin increase the secre‐ agents increase risk for gastric mucosal ulceration. tion of gastric acid. This compounded by dietary indiscretion and injudicious ingestion of nonsteroidal inflammatory agents increase risk for gastric mucosal ulceration.

Figure 2. The secretion of central neurotransmitters and hormones such as cortisol and prolactin increase the

The association between psychological status and the gastrointestinal tract is well established. Dr William Beaumont in 1833 demonstrated the influence of psychological stress on gastric mucosal changes. Acclaimed as the Father of Gastric Physiology, Dr Beaumont carried out observations and experiments on an individual known as Alexis St Martin. St Martin had sustained a gastric fistula followed gunshot wound to the stomach, exposing a sliver of gastric mucosa. Beaumont observed that the exposed gastric mucosa instantly reddened when St Martin was angered, connecting the neuroendocrine-emotional status with gastric physiology [25].

Heartburn and dyspepsia are acknowledged symptoms related with psychological and mood disorders. Gastro-oesophageal reflux disease can be anatomically traced back to dysfunction of the gastro-oesophageal junction, however psychological factors can play an important role in the exacerbation of heart-burn. Well defined personality factors modulate the effect of stress on the gastro-oesophageal junction, just as they can influence the perception and assessment of symptoms. Gastric and small intestinal motor disorders and stomach acid hypersecretion, interact with psychological and neurohormonal resulting in the pathogenesis of dyspepsia. Greater proximal extension of acid during reflux episodes has been demonstrated in patients with proven gastro-oesophageal reflux disease. These patients describe a shorter history of symptom onset and worse anxiety scores. Endoscopic investigation depict findings compatible with gastritis [26].

Altered secretion of gastric acid in the stomach has been linked with a vast array of modulators supporting the neuro-endocrinological connection. Central neurotransmitters and/or neuro‐ modulators may excite or inhibit gastric acid secretion. Excitatory neuro-endocrine modulators such as gamma-aminobutyric acid (GABA), acetylcholine, thyrotropin releasing hormone, oxytocin have been cited. On the contrary, noradrenaline, adenosine, bombesin, calcitoningene related peptide, corticotropin releasing factor, beta-endorphin, neurotensin, neuropep‐ tide Y, insulin-like growth factor II and prostaglandins have been shown to inhibit gastric acid secretion.

Several of these neuro-endocrine mediators have also been noted in 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 were shown to be innervated abundantly by sensory nerve fibres utilizing acetylcholine and norepinephrine as neurotrans‐ mitters [27]. Women with endometriosis have been noted to have lower levels of progesterone in serum in the follicular phase and progesterone levels were inversely correlated to pain scores. Progesterone receptor positive peritoneal lymphocytes of CD56(+) and CD8(+) type were increasing found in advanced endometriosis. Cytokine secretion by peritoneal cells, was higher in cells derived from endometriosis patients and could be further heightened by corticotrophin releasing hormone mediated inflammation. Peripheral corticotrophin releasing hormone increasing with anxiety and emotional stress, might contribute to the peritoneal inflammation present in endometriosis [28,29].

## **6. Gastrointestinal symptoms, the menstrual cycle and endometriosis**

The association between psychological status and the gastrointestinal tract is well established. Dr William Beaumont in 1833 demonstrated the influence of psychological stress on gastric mucosal changes. Acclaimed as the Father of Gastric Physiology, Dr Beaumont carried out observations and experiments on an individual known as Alexis St Martin. St Martin had sustained a gastric fistula followed gunshot wound to the stomach, exposing a sliver of gastric mucosa. Beaumont observed that the exposed gastric mucosa instantly reddened when St Martin was angered, connecting the neuroendocrine-emotional status with gastric physiology

Figure 2. The secretion of central neurotransmitters and hormones such as cortisol and prolactin increase the secretion of gastric acid. This compounded by dietary indiscretion and injudicious ingestion of nonsteroidal inflammatory **Figure 2.** The secretion of central neurotransmitters and hormones such as cortisol and prolactin increase the secre‐ agents increase risk for gastric mucosal ulceration. tion of gastric acid. This compounded by dietary indiscretion and injudicious ingestion of nonsteroidal inflammatory

Factors influencing Gastric Acid Secretion

Hypersecretion of Gastric acid

Nonsteroidal Antiinflammatory Drugs irritating Gastric Mucosa

Increased Prolactin and Cortisol secretion

Dietary Indiscretion

agents increase risk for gastric mucosal ulceration.

Stomach

Secretion of Central Neurotransmitters

174 Dyspepsia - Advances in Understanding and Management

Heartburn and dyspepsia are acknowledged symptoms related with psychological and mood disorders. Gastro-oesophageal reflux disease can be anatomically traced back to dysfunction of the gastro-oesophageal junction, however psychological factors can play an important role in the exacerbation of heart-burn. Well defined personality factors modulate the effect of stress on the gastro-oesophageal junction, just as they can influence the perception and assessment of symptoms. Gastric and small intestinal motor disorders and stomach acid hypersecretion, interact with psychological and neurohormonal resulting in the pathogenesis of dyspepsia. Greater proximal extension of acid during reflux episodes has been demonstrated in patients with proven gastro-oesophageal reflux disease. These patients describe a shorter history of symptom onset and worse anxiety scores. Endoscopic investigation depict findings compatible

Altered secretion of gastric acid in the stomach has been linked with a vast array of modulators supporting the neuro-endocrinological connection. Central neurotransmitters and/or neuro‐ modulators may excite or inhibit gastric acid secretion. Excitatory neuro-endocrine modulators such as gamma-aminobutyric acid (GABA), acetylcholine, thyrotropin releasing hormone,

[25].

with gastritis [26].

An increase in the prevalence of gastro-intestimal symptoms are noted around the time of menses and early menopause [30]. These are periods in the reproductive cycle whereby a significant decline or low level of ovarian hormones in serum are noted. These observations suggest that estrogen and progesterone withdrawal may contribute either directly or indirectly to the occurrence of gastrointestinal symptoms and possibly to pathology [30].

Due to significant overlap between the symptoms of endometriosis and symptoms related to endometriotic deposits on the gastrointestinal system, endometriosis has been referred to the great masquerader. Moreover the menstrual cycle may also impact on gastrointestinal function. As confirmed in the general literature, the presence of frequent menstruation in our study in patients with endometriosis increased the likelihood of related gastrointestinal symptoms.

Abdominal symptoms are significantly more pronounced at the beginning of the menstrual cycle in the follicular phase [14]. 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 complaining of bowel motility symp‐ toms indicate that stomach pain was higher throughout the menstrual cycle. Patients with endometriosis complained of cramping pain more commonly in the perimenstrual phase [31].

Intestinal motility disorders may be associated with the genesis of endometriosis and con‐ versely endometriosis may influence intestinal motility. Preclinical studies have shown significantly more colonic damage, myeloperoxidase activity, and leucocyte count numbers than controls did. Increased tension in the longitudinal muscle correlated with leuccytosis and colonic damage. Mabrouk et al have shown that in deep infiltrating endometriosis, internal anal sphincter tone was increased in 20 of 25 patients. Responses to a defaecatory function questionnaire, indicated that incomplete evacuation was the most common symptom [32].

The presentation of endometriosis may mimic that of inflammatory bowel disease. 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 intimately related to prostaglandin levels. Elevated prostaglandin levels increase contractility of intestinal smooth muscle resulting in diarrhoea

Functional Gastrointestinal Symptoms in Women with Pelvic Endometriosis

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177

There is critical importance in the clinical distinction between the diagnosis of endometriosis and inflammatory bowel disease. Nonsteroidal anti-inflammatory drugs are administered to relieve the symptoms of dysmenorrhoea in the presence and absence of endometriosis. However Nonsteroidal anti-inflammatory drugs are contraindicated in inflammatory bowel

Dietary components in relation to symptomatic Endometriosis and Gastrointestinal symptoms

Psychological stress is also related to injudicious ingestion of dietary components that may irritate the gastrointestinal tract. Somatization, state and trait anxiety and binge eating are

Nutrition research suggests that vitamins, minerals, and other dietary components are important underpinnings of general physical and mental health. Moreover, dietary modifica‐ tion may even be useful in treating mood disorder by providing a more favourable risk-benefit

The body mass index of women who experience depression is significantly higher than controls. Meta-analyses confirm a reciprocal link between depressive states and obesity. Selfconfirmed depression, and clinically diagnosed depression are strongly associated with high

Anxiety states have been shown to result in excessive ingestion of benzodiazepines, relaxing lower oesophageal sphincter pressure and subsequently facilitating gastro-oesophageal reflux. Depression treated with clomipramine was associated with an increased risk of oesophageal

Moreover, depression and its therapy were found to be predictive of developing obesity. Early during the first 6 weeks of nortriptyline treatment, weight gain commences, reaching on

Chronic consumption of nonsteroidal anti-inflammatory agents to counter endometriosisinduced dysmenorrhoea and menorrhagia may lead to ulceration of the gastric mucosa. The degree of nonsteroidal anti-inflammatory gastropathy may be severe enough to develop gastric and duodenal ulceration. It appears that there is sufficient evidence to indicate that administration of nonsteroidal anti-inflammatory drugs could be considerably attenuated and adverse effects, avoided if medical practitioners were persuaded to change their prescribing

**6.1. Pharmacological treatment of endometriosis and gastrointestinal symptoms**

reflux (OR 4.6, 95% CI 2.0-10.6) in a duration- and dose-dependent manner [39].

average 1.2 kg at 12 weeks with a resultant 0.44% increase in body mass index [40].

disease due to the risk of exacerbation of inflammatory bowel disease.

significant predictors of coexistent gastrointestinal disorders.

ratio than contemporary psychotropic agents [38].

and abdominal pain.

body mass index.

practices [41].

Premenstrual symptoms may be affected by dietary components. Soy products have not been shown to alter Moos Menstrual Distress scores significantly during premenstrual phase [33]. However the ingestion of total saturated and monounsaturated fats were significantly correlated with change in Moos Menstrual Distress scores which assesses a number of premenstrual and menstrual symptomatology and subscale 'pain' in the premenstrual phase after controlling for the covariates. The consumption of cereals/potatoes/starches was signifi‐ cantly inversely correlated with a change in total Moos Menstrual Distress scores in the premenstrual phase [33].

Presumably due to hormonal and menstrual differences twice as many women as men seek health services for irritable bowel syndrome as men. The presence of dyspepsia in women, was found to be a significant independent risk factor for new-onset irritable bowel syndrome ( [OR] = 2.14; 95% CI, 1.56–2.94). The majority of women with irritable bowel syndrome requesting medical consultation are of reproductive age experiencing the hormonal fluctua‐ tions of the menstrual cycle. However, after the age of 50 most population surveys have reported a decline in the prevalence of irritable bowel syndrome[34]. Both oestrogen and progesterone influence 5-hydroxytryptamine, an amine which is known to effect intestinal motor-sensory function. During menstruation where oestrogen 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 diarrhoea were similar to healthy controls [35]. Compared to males, females with irritable bowel syndrome more commonly display non-painful gastrointestinal symptoms, constipation and somatic discom‐ fort. There appear to be different gender-related pathways in sympathetic nervous system responses to rectosigmoid stimulation. In a study by Chang et al 58 patients with irritable bowel syndrome underwent barostat-assisted distensions of the rectum and sigmoid colon. Women with irritable bowel syndrome had significantly lower rectal discomfort thresholds compared with men with irritable bowel syndrome and healthy women who were the least sensitive. There were no significant differences in rectal discomfort thresholds between men with irritable bowel syndrome and healthy men. In both irritable bowel syndrome and control groups, women demonstrated significantly lower discomfort thresholds after noxious sigmoid stimulation (P<0.01) compared to men. [36].

Oral contraception results in 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 complain of less cognitive, anxiety, and depression symptoms (p < 0.05) but no differences were seen for most symptoms of irritable bowel syndrome [37]. There may be a differential effect of oral contraception depending on gastrointestinal symptom pattern.

The presentation of endometriosis may mimic that of inflammatory bowel disease. 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 intimately related to prostaglandin levels. Elevated prostaglandin levels increase contractility of intestinal smooth muscle resulting in diarrhoea and abdominal pain.

significantly more colonic damage, myeloperoxidase activity, and leucocyte count numbers than controls did. Increased tension in the longitudinal muscle correlated with leuccytosis and colonic damage. Mabrouk et al have shown that in deep infiltrating endometriosis, internal anal sphincter tone was increased in 20 of 25 patients. Responses to a defaecatory function questionnaire, indicated that incomplete evacuation was the most common symptom [32].

Premenstrual symptoms may be affected by dietary components. Soy products have not been shown to alter Moos Menstrual Distress scores significantly during premenstrual phase [33]. However the ingestion of total saturated and monounsaturated fats were significantly correlated with change in Moos Menstrual Distress scores which assesses a number of premenstrual and menstrual symptomatology and subscale 'pain' in the premenstrual phase after controlling for the covariates. The consumption of cereals/potatoes/starches was signifi‐ cantly inversely correlated with a change in total Moos Menstrual Distress scores in the

Presumably due to hormonal and menstrual differences twice as many women as men seek health services for irritable bowel syndrome as men. The presence of dyspepsia in women, was found to be a significant independent risk factor for new-onset irritable bowel syndrome ( [OR] = 2.14; 95% CI, 1.56–2.94). The majority of women with irritable bowel syndrome requesting medical consultation are of reproductive age experiencing the hormonal fluctua‐ tions of the menstrual cycle. However, after the age of 50 most population surveys have reported a decline in the prevalence of irritable bowel syndrome[34]. Both oestrogen and progesterone influence 5-hydroxytryptamine, an amine which is known to effect intestinal motor-sensory function. During menstruation where oestrogen 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 diarrhoea were similar to healthy controls [35]. Compared to males, females with irritable bowel syndrome more commonly display non-painful gastrointestinal symptoms, constipation and somatic discom‐ fort. There appear to be different gender-related pathways in sympathetic nervous system responses to rectosigmoid stimulation. In a study by Chang et al 58 patients with irritable bowel syndrome underwent barostat-assisted distensions of the rectum and sigmoid colon. Women with irritable bowel syndrome had significantly lower rectal discomfort thresholds compared with men with irritable bowel syndrome and healthy women who were the least sensitive. There were no significant differences in rectal discomfort thresholds between men with irritable bowel syndrome and healthy men. In both irritable bowel syndrome and control groups, women demonstrated significantly lower discomfort thresholds after noxious sigmoid

Oral contraception results in 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 complain of less cognitive, anxiety, and depression symptoms (p < 0.05) but no differences were seen for most symptoms of irritable bowel syndrome [37]. There may be a differential effect of oral contraception depending on gastrointestinal symptom pattern.

premenstrual phase [33].

176 Dyspepsia - Advances in Understanding and Management

stimulation (P<0.01) compared to men. [36].

There is critical importance in the clinical distinction between the diagnosis of endometriosis and inflammatory bowel disease. Nonsteroidal anti-inflammatory drugs are administered to relieve the symptoms of dysmenorrhoea in the presence and absence of endometriosis. However Nonsteroidal anti-inflammatory drugs are contraindicated in inflammatory bowel disease due to the risk of exacerbation of inflammatory bowel disease.

Dietary components in relation to symptomatic Endometriosis and Gastrointestinal symptoms

Psychological stress is also related to injudicious ingestion of dietary components that may irritate the gastrointestinal tract. Somatization, state and trait anxiety and binge eating are significant predictors of coexistent gastrointestinal disorders.

Nutrition research suggests that vitamins, minerals, and other dietary components are important underpinnings of general physical and mental health. Moreover, dietary modifica‐ tion may even be useful in treating mood disorder by providing a more favourable risk-benefit ratio than contemporary psychotropic agents [38].

The body mass index of women who experience depression is significantly higher than controls. Meta-analyses confirm a reciprocal link between depressive states and obesity. Selfconfirmed depression, and clinically diagnosed depression are strongly associated with high body mass index.

#### **6.1. Pharmacological treatment of endometriosis and gastrointestinal symptoms**

Anxiety states have been shown to result in excessive ingestion of benzodiazepines, relaxing lower oesophageal sphincter pressure and subsequently facilitating gastro-oesophageal reflux. Depression treated with clomipramine was associated with an increased risk of oesophageal reflux (OR 4.6, 95% CI 2.0-10.6) in a duration- and dose-dependent manner [39].

Moreover, depression and its therapy were found to be 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 [40].

Chronic consumption of nonsteroidal anti-inflammatory agents to counter endometriosisinduced dysmenorrhoea and menorrhagia may lead to ulceration of the gastric mucosa. The degree of nonsteroidal anti-inflammatory gastropathy may be severe enough to develop gastric and duodenal ulceration. It appears that there is sufficient evidence to indicate that administration of nonsteroidal anti-inflammatory drugs could be considerably attenuated and adverse effects, avoided if medical practitioners were persuaded to change their prescribing practices [41].
