Key points

• •
  

  Epidemiological studies show that the incidence of gastroparesis in women is four times higher than men.

  
  
• •
  

  Female sex hormones fluctuate during different hormonal stages including the menstrual cycle, pregnancy, and menopause raising the theory that differences in gonadal steroid hormones may play a role in the pathophysiology of the female predominance in gastroparesis.

  
  
• •
  

  Estrogen can modulate the biochemical function of neuronal nitric oxide synthase (nNOS), the primary source of nitric oxide (NO) which helps regulates GI tract motility. Chronic estrogen deficiency in women impairs nNOS-mediated gastric motility which can result in gastroparesis.

  
  
• •
  

  Serotoninergic signaling plays a critical part in the motor, sensory, and secretory roles of GI motility. Alterations in serotonin expression may be partly responsible for gender differences observed in gastroparesis and in other functional gastrointestinal disorders.

Introduction

Gastroparesis is a disorder of the stomach manifested by delayed gastric emptying with associated symptoms of nausea, vomiting, bloating, early satiety, upper abdominal pain, and postprandial fullness. Women make up the significant majority of patients with gastroparesis with a female to male ratio of 4:1 . Epidemiologically, 67–88% of patients with gastroparesis are female with a mean age of diagnosis of 41 years, with a wide range of 4 – 86 years . In every subtype of gastroparesis, females predominate – whether it be diabetic, idiopathic, post-surgical, post-viral, among others. The mechanism or biological basis behind why females are more susceptible to developing gastroparesis compared to males is not well understood and conflicting findings are found in the literature . For example, some studies suggest that females have slower gastric emptying compared to males , yet other studies have found no significant difference .

Before the 1990s, studies published on gastric emptying assumed that both men and women had identical gastric emptying rates, and many studies did not even mention the sex of subjects because gender was not considered to be relevant in this matter . In the 1980s and 1990s, research begin to emerge showing that gastric emptying is indeed very much affected not only by gender – but also by menopausal status, phase of menstrual cycle, and pregnancy with sex hormonal differences suspected to play a role in gastric motility . It is well established that female sex hormones (i.e. estrogen, progesterone) play a critical role in reproductive health. Nevertheless, emerging evidence demonstrates that sex hormones can also influence GI motility, with estrogen and progesterone receptors found throughout the GI tract . Sex steroid hormones vary throughout different female hormonal phases which can alter GI motility through various proposed mechanisms including loss of neuronal nitric oxide (nNOS) expression and elevated oxidative stress . Premenopausal females, who normally have higher levels of estrogen and progesterone, have been shown to have slower gastric emptying compared to postmenopausal counterparts or to age-matched males . Pregnancy further changes sex hormone levels with resultant increases in both estrogen and progesterone. After menopause, both estrogen and progesterone levels drop significantly. Since fluctuations in female sex hormones exist during different female hormonal stages (menstrual cycle, pregnancy, menopause), the clinician should be mindful of differences in gastric emptying that may exist during each of these phases in both the healthy and gastroparetic patient.

It is important to have a basic understanding of the menstrual cycle and how the different phases, with concordant variations in ovarian sex steroid hormones, might affect GI motility ( Fig. 37.1 ). The menstrual cycle can be divided into two phases, the follicular phase (approximately days 1–14) and the luteal phase (approximately days 15–28) . Menses (typically days 1–6) occurs early during the follicular phase when estrogen and progesterone levels are at their lowest, and shedding of the endometrial lining occurs if fertilization of an oocyte did not occur. During the follicular phase, estrogen levels slowly begin to rise. The high estrogen levels trigger ovulation (release of a mature oocyte from an ovarian follicle), after which estrogen levels fall precipitously. Ovulation occurs mid-cycle, (typically days 15–18) and marks the beginning of the luteal phase. Early during the luteal phase, estrogen levels rise a second time but progesterone levels secreted by the corpus luteum (remains of the ovarian follicle that released a mature oocyte) rise to even higher levels in order to prepare and maintain the endometrial lining for possible oocyte fertilization and implantation. If an oocyte is not fertilized, then the corpus luteum stops secreting progesterone and it degenerates. The menstrual cycle then repeats itself.

Phases in Menstrual Cycle.

Some , but not all studies have demonstrated that the different phases in the menstrual cycle influence gastric motility with slower gastric emptying occurring during the luteal phase when estrogen and progesterone levels are significantly elevated. Several studies have shown that progesterone inhibits smooth muscle function. A study by Gill et al. on 7 normally-menstruating women who had undergone bilateral fallopian tube ligations observed impairment of gastric emptying during the luteal phase of their menstrual cycle which correlated with elevated levels of progesterone . An in vitro study showed that the combination of estrogen and progesterone had inhibitory effects on the smooth muscle of the lower esophageal sphincter, pylorus, and small bowel which led to reduced gastrointestinal contractility . Other in vitro studies have also shown that pretreatment with progesterone affected the contractile muscular responses of the esophagus, stomach, colon, and gallbladder . Similarly, an in vivo study in rats showed that a combination of estradiol-17β (E ₂ ) and progesterone – or just E ₂ alone, both inhibited gastric emptying . Similarly, studies by Gangula et al. showed that gastric emptying in rats was slower during the estrus cycle when estrogen levels were elevated . All of these studies suggest that estrogen and progesterone have inhibitory effects on gastric motility, and therefore might predict slower gastric motility during the luteal phase when these female hormone levels are highest.

Though gastric motility studies during pregnancy are scarce, the few studies that do exist in the literature show conflicting results. Some reports show no significant delay in gastric emptying during pregnancy , while others do . One should take into account that these four referenced studies that showed a delay in gastric emptying had limitations: the Simpson et al. study was performed late in pregnancy when mechanical factors might limit gastric emptying (i.e. enlarging uterus pushing on the stomach); Ryan et al. used a liquid meal in pregnant guinea-pigs, and liquid gastric emptying tests are not standard because the normal emptying of liquids is usually maintained despite very severe gastroparesis in solids; Wald et al. not only performed their study late in pregnancy but also measured gastric emptying by monitoring breath hydrogen concentrations after a liquid lactulose meal ; Although Chiloiro et al. did not show significant changes in gastric emptying during the first trimester, orocecal transit time was significantly longer during the third trimester largely attributed to increased progesterone levels (method: monitoring of breath hydrogen concentrations) . Nonetheless, one of the main arguments in all of these studies that showed impaired gastric motility is that gastric emptying changes during pregnancy might occur because of increased circulating levels of progesterone and estradiol. Interestingly, nauseated pregnant women in their first trimester have been found to have gastric dysrhythmias by electrogastrogram, which correlated with increased levels of estradiol and progesterone . Nonpregnant women who received exogenous estradiol and/or progesterone to levels equivalent in the first trimester of pregnancy also experienced nausea with similar dysrhythmias evoked on electrogastrography. This suggests that elevated levels of progesterone and estrogen can mimic GI symptoms experienced during pregnancy and may concomitantly cause gastric dysrhythmias.

Menopause and sex hormone replacement have also been shown to affect GI motility. During menopause, estrogen and progesterone levels significantly drop. Datz and colleagues found that premenopausal women had slower gastric emptying rates compared to postmenopausal women . Additionally, Hutson et al. showed that gastric emptying in postmenopausal subjects improves and approximates a trend similar to that in men . On the other hand, women taking sex hormone replacement with estrogen and progesterone (either premenopausal or postmenopausal women) exhibited delayed gastric emptying of solids compared to age-matched men. To further elaborate on this study, gastric emptying was measured using a dual-isotope technique in 20 men, 18 premenopausal women, 14 postmenopausal women, and 8 postmenopausal women taking hormone replacement with estrogen and progesterone. Gastric emptying of liquids was slower for all women compared to men including premenopausal women, postmenopausal women, and postmenopausal women taking oral estrogen and progesterone ( P <.025, <.05, and <.025 – respectively). Gastric emptying of solids was slower for both premenopausal women and postmenopausal women on sex hormone replacement compared to men ( P <.025 and <.05). In contrast, postmenopausal women not on sex hormone replacement emptied solids at a rate similar to men. Therefore, menopausal status and hormone replacement appear to influence gastric emptying via variable inhibitory effects of estrogen and progesterone. Interestingly, estradiol-17β, the primary female reproductive hormone and most active estrogen has been proposed to have protective effects in the GI tract since it has been shown to suppress oxidative stress and increase antioxidants . Therefore, hormone replacement with estrogen has been suggested as a possible potential remedy in gastroparesis since hormone therapy might help restore impaired nitrergic-mediated gastric motility .

There are several gender-related physiologic differences which might also explain some of the gender disparities in baseline gastric motility. For example, women have been found to have decreased antral contractility, prolonged fundic relaxation, altered enteric transmission, and visceral hypersensitivity compared to males . Also, healthy women are disproportionately more symptomatic than men simply because their stomachs empty slower . In a case series of 243 patients with idiopathic gastroparesis, 88% of these patients were female, and they were noted to have more severe nausea, satiety, and overall gastroparesis symptoms compared to males . In a telephone survey of 21,128 adults with upper gastrointestinal disorders, females were noted to more commonly report symptoms of early satiety and nausea compared to males. It is possible that these physiologic differences might just create a lower reserve for females, designating them with different “normal” gastric function parameters and thereby creating a lower insult threshold making them more susceptible to gastroparesis. Another hypothesis by Zia and Heitkemper is that the absolute level of progesterone and estrogen may not be as important to influencing GI motility as the rate of change in these female hormones during the menstrual cycle .

To bring some perspective to this chapter, the landmark 4-hour gastric emptying protocol described by Tougas et al. with a 99Tc-labeled low-fat, egg-white meal with imaging at 0, 1, 2, and 4 hours did not show any end-point variability attributed to gender in 123 healthy volunteers (60 women, 63 men) . This gastric scintigraphy protocol is the gold standard to evaluating gastric emptying (GE) because of its standardized, reliable, sensitive, and objective approach. Consensus guidelines based on this study were defined by The Neurogastroenterology and Motility Society (ANMS) and the Society of Nuclear Medicine . In the Tougas et al. study, there was initially significantly greater retention in female subjects at 1 and 2 hours compared to males ( P <.002 and .0001, respectively), with similar findings reported in other studies . However, although GE was initially significantly more rapid in men at 60 and 120 minutes, it was ultimately comparable in both men and women at 4 hours. In retrospect, Tougas and colleagues recognize in their study that they did not control for phases of the menstrual cycle in premenopausal women. Furthermore, they mention that their study did not have sufficient power to detect differences in GE between men and women with increasing age. Although this study provides an excellent GE clinical tool, it does not have the predictive utility to further define pathophysiological gender differences that exist in GE as also acknowledge by the authors. We speculate that gender differences may be hidden in this landmark study, and it could be that 4-hours might eventually overcome hormonal variations between males and females. Perhaps an area of future study might include measuring GE differences between men and women at 2 hours while accounting for differences in menstrual cycle (follicular versus luteal phase) and further separating women into premenopausal and menopausal subsets and also being mindful of whether or not they are on hormone supplements. Of note, the ANMS does suggest limiting GE testing in women during the first week of the menstrual cycle when estrogen and progesterone levels are lowest.

The ensuing chapter will now discuss several potential molecular similarities and differences in gastroparesis between men and women focusing on demography, cellular changes, and molecular pathways.

Epidemiology of gastroparesis

Population-based epidemiologic data concerning gastroparesis at the national level is lacking. However, there are few reports based on community studies and hospitalization records and they include the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Gastroparesis Clinical Research Consortium (GpCRC) with the goal of performing clinical, epidemiological, and therapeutic research in gastroparesis. Also, a large population-based epidemiological study performed on 3604 residents with potential gastroparesis from Olmsted County, Minnesota described the incidence, prevalence, and outcome of gastroparesis in this community, and the incidence and prevalence of gastroparesis in women was four times higher compared to men .

In a separate study, it was reported that 88% of 243 patients with idiopathic gastroparesis were young females . Among these females, 46% were overweight, 19% had an infectious prodrome, and 50% had an acute onset of symptoms. This study also demonstrated that variation in the patient population (sex, age, and weight) affected disease severity. In a case series by McCallum et al. the causes of gastroparesis in 146 patients (82% female) were 36% idiopathic, 29% diabetic, 13% post-surgical, 7.5% Parkinson’s disease, and 4.8% collagen disease . In another study by Dickman et al., the prevalence of diabetic gastroparesis (DG) was found to be particularly high in obese females from a large population of patients in Israel with type 2 diabetes mellitus (T2DM) .

Using population statistics and the state department database, it was reported that there is significant variability in admissions, interventions, and outcomes for gastroparesis . The authors suggested that socioeconomic variables are the contributing factors for this variability. Hirsch et al. analyzed trends in gastroparesis-related emergency department (ED) visits from 2006 to 2013 and reported that the number of patients with DG who visited the ED increased 148% and was comprised predominantly of women . A recent study reported by Syed et al. using the medical records of different hospitals in the USA from 1999 to 2014 comprising over 43 million patients noted that the absolute number of cases of gastroparesis is greater in T2DM and 1.5 times higher in females than in males. It is evident from these reports that there is a female predominance in all subtypes of gastroparesis.

Sex hormones differences in gastroparesis

As reviewed in the first part of this chapter, the preponderance of gastroparesis in women suggests that estrogen might play a critical role in the development and progression of gastric motility dysfunction. Research from our group demonstrated that elevated estrogen levels promoted the development of gastroparesis in both male and female rats . Contrary to these observations, Matos et al. . demonstrated that high progesterone and low estrogen levels are associated with slow gastric emptying in female rats. This was further supported by the observation that chronic deficiency of circulating estrogen in FORKO mice (mice lacking the follicle stimulating hormone receptor which causes complete loss of ovarian estrogen production) causes gastroparesis by altering neuronal nitric oxide synthase (nNOS) function . The conflicting results observed in published reports could be due to time of experimentation after diabetes development or species-specific differences. Although there are conflicting reports with regard to the major role of estrogen function, these studies predominantly suggest that estrogen may contribute to the development of gastroparesis in women.

Two estrogen receptors, α (ERα) and β (ERβ) have been identified. While estrogen receptor subtypes share mechanistic similarities, they are functionally distinct. For example, ERα knockout mice show quite a different phenotype when compared to ERβ knockout mice , and ERβ can antagonize ERα-dependent transcription . We reported elevated expression of ERα in female gastroparetic rats . In contrast, we found that the ERβ receptor is upregulated in male gastroparetic rats . Collectively, these data suggest that gender-specific up-regulation of these two receptors might be responsible for the development of gastroparesis between males and females. The molecular mechanisms of ERα and ERβ-mediated signaling deserves further investigation. In addition, this study needs to be replicated in humans to determine whether the phenomenon is universal.

Although reduced testosterone is associated with T2DM and insulin resistance, it has not been shown to be associated with the development of gastroparesis in either females or males . Studies related to T1DM and hypogonadism (reduced testosterone production), however, have yielded inconsistent results. For example, Holt et al. . reported that development of type 1 diabetes mellitus (T1DM) in men is not associated with hypogonadism, whereas other reports show that a decreased testosterone level is a factor in the development of T1DM . Although there is substantial evidence that the female sex hormone estrogen contributes to the development of gastroparesis , there is no evidence to date of testosterone involved in the development of gastroparesis in males. Our results show no statistical difference in testosterone levels between diabetic rats and DG male rats, suggesting that testosterone is not responsible for the development of gastroparesis . Similar to our observation, Chen et al. reported that testosterone had no influence on gastric emptying . One of the most important factors that affect testosterone levels is the aromatase enzyme. Aromatase converts testosterone to estrogen, which subsequently increases estrogen levels. In the same study, we found no difference in circulatory levels and pyloric tissue levels of aromatase between diabetic rats and DG male rats. Based on our studies and many others, testosterone does not appear to have an impact on gastroparesis.

Nitric oxide (NO) signaling and gastroparesis

Nitrergic system dysfunction has been reported as a proposed mechanism in gastric motility gender-related differences. The nitrergic system refers to the inhibitory enteric neurons embedded in the muscle of the gut wall which play a critical role in gastric motility (gastric accommodation, pyloric relaxation) . Neuronal NO synthase (nNOS) which is expressed in inhibitory enteric neurons, produces NO, the main nonadrenergic noncholinergic inhibitory neurotransmitter that leads to smooth muscle relaxation . “Nitrergic signaling” refers to the release of NO from these inhibitory enteric neurons which play a critical role in the regulation of muscle tone in the lower esophagus, antrum, pylorus, sphincter of Oddi , as well as gastric accommodation and intestinal peristalsis in response to food .

Nitric oxide (NO) production from l -arginine by nitric oxide synthase (NOS) enzymes is a very complicated reaction in the body involving many steps with many cofactors. NO signaling is primarily regulated by three distinctive NOS isoform enzymes: endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) . nNOS is ubiquitously expressed in gastric neurons and plays a pivotal role in various parts of the GI tract. The nNOS gene encodes a protein product of approximately 160 kDa. nNOS has a unique protein structure compared to other NOSs with an N-terminal extension of 200 amino acids which has been designated as the PDZ domain . The function of this domain is to interact with other proteins, to participate in the sub-compartmentalization of the nNOS protein in the cell, and to participate in the formation of active nNOS dimers . Its functions are tightly regulated by post-translational modifications including serine phosphorylation, ubiquitination, and SUMO-lyation . As a result of gene splicing, three different nNOS proteins are expressed in the gut: nNOSα, nNOSβ, and nNOSγ. The only catalytically active isoform in the gut is nNOSα . Studies have demonstrated that nNos ^−/− mice had gastric dilation, gastric muscle thickening, and delayed emptying of solids and liquids compared to wild- type and eNOS-deficient mice . Furthermore, GI motility impairment in nNos ^−/− mice is linked with pyloric sphincter dysfunction .

NO signaling is one of the mechanisms shown to be regulated by estrogen. A role for estrogen in the regulation of nNOS and in the pathogenesis of gastroparesis came from the observation that estrogen delays gastric emptying and decreases nNOS expression in female diabetic rats . We reported that there is a gender-specific impairment of gastric nNOSα dimerization in rats with streptozotocin-induced DG and its post-translational modification by estrogen . Our findings correlate with the reported observations of other investigators. For example, Shah et al. demonstrated that estrogen is responsible for increased gastric nNOS expression and nitrergic relaxation . It was reported from the same laboratory that in pregnant rats, decreased motility was mediated by elevated sex steroid hormones and NO . Impairment of the nitrergic system has abeen observed to a great extent in female streptozotocin-induced diabetic rats compared to males (impaired nNOSα dimerization and nitrergic relaxation) . In another study, DG rats were found to have a decrease in nNOS expression and dimerization, nitrergic relaxation, and increased intragastric pressures . These results were further substantiated by the observation that tetrahydrobiopterin (BH4) , a cofactor of nNOS and sepiapterin , restored gastric emptying and nNOS expression in female DG rats which suggests the possibility that these molecules might help reverse delayed gastric emptying. Interestingly, chronic estrogen deficiency negatively modified the function of nNOS in a FORKO mouse model, thereby contributing to the development of DG . Taken together, aforementioned studies suggest that gastric motility is slower in females and this might be due to the estrogen-mediated regulation of nNOSα, thereby decreasing the production of NO. These studies show that females have greater vulnerability to developing gastric-motility impairments compared to males in the setting of nitrergic dysfunction.

Evidence of an impaired nitrergic system has also been noted in animal models and patients with functional GI disorders (FGID) which are also marked by female predominance . Therefore, females might have a greater dependency on the nitrergic system than males do with diabetes seemingly affecting nitrergic nerves to a greater degree in females . Nitrergic dysfunction in patients with FGID has been attributed to low-grade inflammatory changes in the small bowel (lymphocyte infiltration), one of several proposed underlying pathophysiologic disturbances observed in this disease. Some studies have showed improvement in nitrergic dysfunction after treatment with aminoguanidine, a selective inhibitor of the iNOS enzyme (inhibiting iNOS subsequently decreases NO production) . Masaoka and colleagues evaluated nitrergic dysfunction and intestinal inflammation in normoglycemic diabetes-prone rats and observed that intestinal dysmotility was accompanied by neuronal loss and nNOS mRNA expression by immunohistochemistry . They demonstrated that treatment with aminoguanidine counteracted inflammation-induced nitrergic dysfunction and prevented intestinal dysmotility, independent of hyperglycemia . Tegaserod, an aminoguanidine indole 5-HT ₄ receptor partial agonist approved for the treatment of constipation-predominant IBS, has been shown to markedly accelerate gastric emptying in some healthy patients and small intestinal transit and has also been shown to stimulate postprandial antral and intestinal motility . Effects of aminoguanidine-like agents like Tegaserod may therefore be able to exert promotile effects on patients with both gastroparesis and FGID. Furthermore, the presence of nitrergic dysfunction in FGID might be a causal link between the gender bias that exists in both FGID and gastroparesis.

Interstitial cells of Cajal

Interstitial cells of Cajal (ICC) are pacemaker cells located in the greater curvature of the stomach and are critical components of GI motility by transducing nitrergic and cholinergic signals to smooth muscle cells . ICC generate spontaneous electrical slow waves and transmit these waves to smooth muscle cells in the gut to generate phasic contractions and peristalsis. Absence or reduction in the number of ICC or alteration of their structure has a dramatic effect on GI motility. Results from animal models of diabetes as well as in humans suggest that DG involves the depletion of ICC . For example, a study in nonobese diabetic (NOD)-mice suggested that damage to the ICC was associated with significant disruption in slow wave activity and resulted in delayed gastric emptying . Studies in db/db mice (an animal model of type II diabetes) also showed loss of ICC . In human studies, histologic examination showed that ICC populations are lower in the stomachs of DG compared to non-DG individuals . From these studies, it is clear that GI motility requires normal distribution and function of ICC in both males and females. However, there is limited data that addresses the gender difference on ICC loss. Thus, careful characterization of gender-related changes in humans is critical for proper evaluation and understanding of pathologic changes in gastroparesis especially those that affect women.

Serotonergic signaling and gastroparesis

Serotonin (5-HT) is best known for its role as a brain neurotransmitter involved in the modulation of human emotions including anger, mood, sleep, appetite, and metabolism. However, it is estimated that > 90% of the body’s serotonin is produced by enterochromaffin cells in the small intestine in response to food . 5-HT affects many gut functions including motility, secretion, sensation and also promotes the development and maintenance of the enteric nervous system by neurogenesis both prenatally and as an adult . Activity of 5-HT is modulated by 5-HT receptors which are made up of seven families (5-HT _1–7 ). These receptors belong to heptahelical G-protein coupled receptors, and five of the seven known families play a vital role in GI function and are detected in enteric neurons: 5-HT ₁ , 5-HT ₂ , 5HT ₃ , 5-HT ₄ , and 5-HT ₇ . These 5HT4 receptors are expressed on colonic epithelial cells and mediate both prokinetic and antinociceptic effects .

Altered levels of 5-HT and changes in 5-HT signaling have been observed in several gastrointestinal diseases including gastric dysmotility, functional dyspepsia, irritable bowel syndrome (IBS), celiac disease, gut neuroendocrine tumors, and impaired colonic transit . Knockout mice with loss of tryptophan hydroxylase 1, a rate-limiting enzyme involved in the production of 5-HT, led to almost complete cessation of intestinal 5-HT production that subsequently slowed gastric motility . In the pathophysiology of other motility disorders, Talley and colleagues have implied that IBS may be a partly serotonergically-driven problem . Sex hormones have a direct correlation in IBS symptoms . Estrogen, in particular, interacts with serotonin and augments the serotonergic postsynaptic responsiveness in the brain . Serotonin can therefore mediate the effects of estrogen which further influences depression, pain transmission, nausea, headaches and dizziness in the CNS . Hence, sex hormones modulate different levels of the brain-gut axis in IBS and contribute to alterations in motility, immune activation of the intestinal mucosa, visceral sensitivity, and permeability . A review article by Talley et al. describes low grade inflammation and altered intestinal permeability observed in some IBS patients (mostly diarrhea-predominant) which is likely a direct consequence from immune activation (i.e. post-infectious) . These mechanisms likely affect local serotonin release which likely leads to altered motor and sensory functions . This raises the possibility that different serotonergic phenotypes might play a role in the female predominance of gastroparesis.

Selective serotonergic reuptake inhibitors (SSRI)s have been demonstrated to improve gastrointestinal symptoms in patients with functional dyspepsia and IBS though benefits were only observed in depressed patients compared to non-depressed patients . This suggests that altering serotonergic pathways in depressed patients – a significant clinical presentation in functional gastrointestinal disorders also exhibiting female predominance – might reduce their pain threshold by mediating positive effects on emotion and well-being. SSRIs work by reducing the activity of SERT (plasma-lemmal serotonin transporter) – an intracellular transporter that subsequently inactivates 5HT – and therefore reducing SERT activity increases 5-HT availability. Other studies have shown that serotonergic signaling is involved in the regulation of gastric emptying and that using 5HT receptor agonists/antagonists and SSRIs can improve gut motility . In a randomized, placebo-controlled, double-blind, three-way crossover study in 12 healthy male subjects, tegaserod, a 5HT4 agonist, markedly accelerated gastric emptying and small intestinal transit . Metoclopramide, which acts as a combined 5-HT ₄ agonist and dopamine D ₂ antagonist, increased esophageal, antral, and small bowel contractions and also accelerated gastric emptying .

Newer more highly selective 5HT4 agonists may play a role in the treatment of enteric neuropathies given serotonin’s important role as a neuronal growth factor during development of enteric dopaminergic neurons in the fetus . Even as adults, serotonin continues to promote neuroprotection and neurogenesis in the mature enteric nervous system through activation of 5-HT4 receptors . Exciting in vivo studies have shown that Prucalopride, one of the newer 5-HT4 agonists, increases neurogenesis and protects enteric neurons against oxidative stress . In vivo studies are needed to see if Prucalopride and other serotonin-driving agents might help improve gut motility in enteric neuropathic disorders as well as in FGID. Moreover, well-designed large-scale studies are necessary to reveal if different 5-HT phenotypes contribute to gender differences in gastroparesis.

Conclusions

Why women are significantly more vulnerable to developing gastroparesis remains a mystery. Research over the years suggests that multiple mechanisms may play a role including elevated levels of sex steroid hormones, loss of neuronal nitric oxide (nNOS) expression, elevated oxidative stress, slower colonic transit time, and altered serotonergic signaling. Targeting of these pathogenic factors may point towards future therapeutic options to alleviate or even prevent gastroparesis. It is possible that these differences might just create a lower threshold for insult, thereby making women more prone to developing gastroparesis. Females have proven to be a more susceptible host with limited gastrointestinal reserve and resilience resulting in a more difficult recovery course. They have proven to have an increasingly fragile gut with a limited ability to recover from any gastrointestinal insult – whether it be from emotional stress (i.e. PTSD) or physical stress (i.e. inflammation, infection, diabetes, narcotics, vagotomy, autoimmune, endocrine, myogenic, neurogenic, idiopathic). Might women have an innate biological, genetic, and/or environmental susceptibility to developing gastric dysmotility due to fundamental neuromuscular gut variations as observed in the Gangula et al. study with sex-dependent differences noted in the nitrergic system of female streptozotocin-induced diabetic rats? Might females process pain differently and have a lower threshold for visceral hypersensitivity that leads to increased nociceptive awareness? Might women have a more sensitive gut susceptible to aggravation by any injury (i.e. infection, inflammation)? Might women simply have an exaggeration of preexisting inherent differences in gut motility? Might women be disproportionately more symptomatic because their stomachs empty slower compared to males?

In a study by Parkman et al. evaluating the efficacy and safety of metoclopramide administered by nasal spray, symptom improvement was seen in females with diabetic gastroparesis but not in males . In this multicenter, randomized double-blind study of 285 patients with gastroparesis (71% female, 83% type 2 diabetics) were randomized to 4 weeks of placebo or metoclopramide 10 mg or 14 mg sprays TID prior to meals. Symptoms were assessed by using a modified Gastroparesis Cardinal Symptom Index-Daily Diary (bloating, nausea, early satiety, upper abdominal pain). Females experienced significantly improved gastroparesis symptom scores compared with placebo (mean reduction from 10-mg dose, 1.2±1.18; P =.0247; mean reduction from 14-mg dose, 1.3±0.94; P =.0215), whereas symptom scores in males decreased more in the placebo group. Women, but not men showed significant symptom improvement with both metoclopramide nasal spray doses. Other studies have also shown a marked female-response predilection in functional GI disorders such as lubiprostone in constipation-predominant IBS and alosetron for diarrhea-predominant IBS . If females so avidly responded to metoclopramide treatment as noted in this study, their gut might correspondingly be more “eager” and receptive to other prokinetic therapies compared to male counterparts and certain promotility drugs might therefore find a more receptive host in females.

As a clinician, it is important to be cognizant of the sex hormone differences that may impact different female hormonal stages which can subsequently affect GI motility. Sex hormones fluctuate during different female hormonal stages including menstrual cycle, pregnancy, and menopause. Because significant differences in gastric emptying are noted during each of these phases, awareness of physiologic alterations is important when evaluating both healthy and gastroparetic females. Understanding the physiologic differences in gastric motility depending on different female hormonal stages can allow clinicians to tailor treatments and better educate patients. For example, women can be educated that GI symptoms might worsen during the luteal phase of their menstrual cycle and that postmenopausal women tend to have improved symptoms of gastroparesis compared to premenopausal women. Nevertheless, despite our best efforts to better understand the pathophysiology of gastroparesis, an important question that remains unanswered is why gastroparesis affects mostly women. Further studies are needed to further elucidate sex differences in gastric motility.