This article reviews the sex differences in upper gastrointestinal (GI) motility for both healthy and common dysmotility conditions. It focuses on gastroesophageal reflux disease and other esophageal motor disorders for the esophagus and on gastroparesis and accelerated gastric emptying for the stomach. It also describes differences in upper GI motility signs and symptoms during each female hormonal stage (ie, menstrual cycle, pregnancy, perimenopause, menopause) for both healthy participants and those suffering from one of the aforementioned upper GI dysmotility conditions. More research still needs to be conducted to better understand sex differences in upper GI motility.
Key points
- •
Female ovarian hormones (ie, progesterone, estrogen) are one of the main causes for the observed sex differences in upper gastrointestinal motility.
- •
Men have increased stomach acid production and more physiologic gastroesophageal reflux (GERD) than women, possibly explaining the increased complication rates of GERD in men.
- •
Healthy women’s stomachs empty out slower than men. Women also perceive fullness and nausea more quickly and for longer periods of time than men.
- •
Women with gastroparesis tend to be more symptomatic than men. Their symptoms are also less likely to improve over time compared with men.
Introduction
There are known sex differences in gastrointestinal (GI) motility in both healthy and diseased states, likely due to the effect of female hormones. Both estrogen and progesterone receptors are found throughout the GI tract and likely influence its motility. There are several mechanisms that may account for the influence of these hormones on GI motility. In vitro studies suggest that estrogen is needed to prime and enhance the inhibitory effects of progesterone. These hormones also likely mediate GI motility effects by eliciting changes in nitric oxide–containing neurons in the myenteric plexus and by affecting the number and function of mast cells in GI mucosa.
Given the fluctuations of these female hormones during the menstrual cycle, pregnancy, and menopause, including the perimenopausal transition, one may also expect significant differences in GI motility during each of these female hormonal stages. Such differences have in fact been found in some studies and are described in this article. During the menses stage of the menstrual cycle, estrogen and progesterone are at their lowest levels. In the follicular phase that follows, estrogen levels begin to increase. It is this increase that triggers ovulation. Once ovulation has occurred, estrogen levels peak a second time followed by an increase in progesterone levels during the luteal phase to prepare the uterus lining for possible fertilization. If the egg is not fertilized, the corpus luteum degenerates and no longer produces progesterone, followed by a decrease in estrogen levels. The menstrual cycle then repeats itself. Menstruation is considered an inflammatory state characterized by increases in proinflammatory cytokines (eg, tumor necrosis factor-α) and other mediators before menstrual flow. Evidence suggests that the inflammatory response is linked to declining progesterone levels in the late luteal phase. During pregnancy, there is a progressive and substantial increase in progesterone and estrogen. After menopause, the opposite occurs: estrogen and progesterone levels drop significantly. The age at which menopause occurs and the pattern of the drop in hormone levels are variable. This transition is referred to as the perimenopause phase.
Despite the growing evidence that sex differences exist, most practitioners continue to diagnose and treat conditions of GI dysmotility without acknowledging them. Providers often generalize associated risk factors and prognoses of GI dysmotility conditions to both men and women. The effect of female hormonal stages (ie, menses, pregnancy, menopause) on GI motility is also not factored into treatment plans. To more accurately and effectively manage conditions of GI dysmotility for both men and women, providers should better understand the sex differences in both healthy and GI dysmotility conditions. More studies need to be conducted to better understand these sex differences.
This article specifically reviews sex differences in esophageal and gastric motility, first for healthy participants and then for the most common dysmotility conditions. For esophageal conditions, it will focus on gastroesophageal reflux disease (GERD) and other esophageal motor disorders. For gastric conditions, it discusses gastroparesis and accelerated gastric emptying. Although limited by the currently available literature, this article describes any known differences in signs and symptoms during each female hormonal stage for each aforementioned healthy and abnormal condition.
Introduction
There are known sex differences in gastrointestinal (GI) motility in both healthy and diseased states, likely due to the effect of female hormones. Both estrogen and progesterone receptors are found throughout the GI tract and likely influence its motility. There are several mechanisms that may account for the influence of these hormones on GI motility. In vitro studies suggest that estrogen is needed to prime and enhance the inhibitory effects of progesterone. These hormones also likely mediate GI motility effects by eliciting changes in nitric oxide–containing neurons in the myenteric plexus and by affecting the number and function of mast cells in GI mucosa.
Given the fluctuations of these female hormones during the menstrual cycle, pregnancy, and menopause, including the perimenopausal transition, one may also expect significant differences in GI motility during each of these female hormonal stages. Such differences have in fact been found in some studies and are described in this article. During the menses stage of the menstrual cycle, estrogen and progesterone are at their lowest levels. In the follicular phase that follows, estrogen levels begin to increase. It is this increase that triggers ovulation. Once ovulation has occurred, estrogen levels peak a second time followed by an increase in progesterone levels during the luteal phase to prepare the uterus lining for possible fertilization. If the egg is not fertilized, the corpus luteum degenerates and no longer produces progesterone, followed by a decrease in estrogen levels. The menstrual cycle then repeats itself. Menstruation is considered an inflammatory state characterized by increases in proinflammatory cytokines (eg, tumor necrosis factor-α) and other mediators before menstrual flow. Evidence suggests that the inflammatory response is linked to declining progesterone levels in the late luteal phase. During pregnancy, there is a progressive and substantial increase in progesterone and estrogen. After menopause, the opposite occurs: estrogen and progesterone levels drop significantly. The age at which menopause occurs and the pattern of the drop in hormone levels are variable. This transition is referred to as the perimenopause phase.
Despite the growing evidence that sex differences exist, most practitioners continue to diagnose and treat conditions of GI dysmotility without acknowledging them. Providers often generalize associated risk factors and prognoses of GI dysmotility conditions to both men and women. The effect of female hormonal stages (ie, menses, pregnancy, menopause) on GI motility is also not factored into treatment plans. To more accurately and effectively manage conditions of GI dysmotility for both men and women, providers should better understand the sex differences in both healthy and GI dysmotility conditions. More studies need to be conducted to better understand these sex differences.
This article specifically reviews sex differences in esophageal and gastric motility, first for healthy participants and then for the most common dysmotility conditions. For esophageal conditions, it will focus on gastroesophageal reflux disease (GERD) and other esophageal motor disorders. For gastric conditions, it discusses gastroparesis and accelerated gastric emptying. Although limited by the currently available literature, this article describes any known differences in signs and symptoms during each female hormonal stage for each aforementioned healthy and abnormal condition.
The esophagus
Sex Differences in Esophageal Anatomy and Motility in Healthy Participants
Table 1 summarizes the sex differences in esophageal anatomy, motility, sensation, and pH studies. Women may have shorter esophageal sphincter lengths than men. In healthy participants undergoing esophageal manometry, women are more likely to have longer esophageal body contractile duration than men. Studies investigating sex differences in esophageal mechanical pain thresholds have conflicting results, possibly due to differences in balloon distention methods. Although no sex differences in esophageal thermal pain thresholds have been found, women report higher chemical pain thresholds and larger referred pain areas compared with men, possibly reflecting sex differences in central processing of pain to visceral stimuli. In healthy participants undergoing esophageal pH studies, women are found to have decreased physiologic GERD.
| Variable | Healthy Participants (Women vs Men) |
|---|---|
| Anatomy | |
| LES length | Slightly shorter vs no difference |
| Motility | |
| Esophageal body | |
| % Peristalsis | No difference |
| Amplitude | No difference |
| Contractile duration | Longer |
| Velocity | Conflicting: lower vs no difference |
| LES | |
| Resting pressures | Conflicting: higher vs no difference |
| Duration of relaxation | No difference |
| Sensation | |
| Mechanical pain | Conflicting: higher, lower vs no difference |
| Chemical pain | Higher |
| Thermal pain | No difference |
| Referred pain areas | Larger |
| pH studies | |
| % time pH <4 | Lower |
| Total reflux episodes | Lower |
| Episodes >5min | Lower |
| Longest reflux episodes | Shorter |
The Effect of Female Hormonal Stages on Esophageal Motility
Table 2 summarizes the known effects of specific female hormonal stages (ie, menses, pregnancy, menopause) on esophageal motility. The authors were unable to find any studies directly examining the effects of the menopause transition on esophageal motility.
| Hormonal Stage | Effect on Esophagus |
|---|---|
| Menstrual cycle | |
| Sensory perception | None |
| LES pressure | Possibly reduced during the luteal phase of the menstrual cycle |
| Distal contraction | None |
| Esophageal emptying | None |
| Pregnancy | |
| LES pressure | Likely reduced |
| Distal contraction | Reduced amplitude |
| % Peristalsis | Reduced % transmitted contractions |
| Menopause | |
| — | Unknown |
During the luteal phase of the menstrual cycle, Van Thiel and colleagues observed a small but significant reduction in lower esophageal sphincter pressures (LESP). However, other studies found no LESP differences during the human menstrual cycle. The clinical significance of a mildly reduced LESP during normal menstrual cycles is likely unimportant. The frequency of symptomatic heartburn does not differ for women during their menstrual cycle. The menstrual cycle also has no effect on esophageal sensory perception, distal esophageal contraction, or esophageal emptying.
LESP are reduced in pseudopregnant women (healthy participants given a potent estrogen followed by progesterone exposure). This finding is discussed further with its clinical implications in the next section. Esophageal dysmotility is rare in pregnancy, although some studies have documented reduced esophageal amplitudes and increased nontransmitted contractions during pregnancy. These patterns may be attributed to gestational hormones and/or, at least later in pregnancy, from increased intragastric pressures from an enlarging uterus.
Sex Differences in Gastroesophageal Reflux Disease
The prevalence of GERD is similar among men and nonpregnant women. The following complications of GERD, however, are more common in men: erosive esophagitis, esophageal ulceration, Barrett’s esophagus and esophageal adenocarcinoma. Similar to the sex differences found in healthy participants, men with GERD also have more acid reflux than women with GERD. Stomach acid production, both basal and maximum output, is increased in men with GERD compared with women with GERD, possibly because of the increased number of stomach parietal cells. In one study, there seems to be only a weak correlation between gastric acid output and GERD severity in both genders. Estrogen may play a role in attenuating esophageal damage through luminal nitric oxide–related pathways. To date, there are no studies on sex differences in transient lower esophageal sphincter (LES) relaxations. Despite having more sequelae of reflux disease though, men have similar hospitalization rates for GERD complications as women.
GERD-associated factors differ among the sexes based on a study by Murao and colleagues. In women, age and lack of exercise are associated factors with GERD, possibly due to fat accumulation in internal organs as women age, resulting in an increase in intra-abdominal pressure. In men, smoking and fewer hours of sleep are associated factors. In both men and women, a hiatal hernia and higher body mass index (BMI) are associated factors. A stronger association between increasing BMI and reflux symptoms is seen in women than in men.
Table 3 outlines known sex differences in the response to common GERD therapies.
| Common Therapies | Known Sex Differences |
|---|---|
| GERD | |
| Lifestyle modifications | No available data |
| Medications | |
| Acid-lowering drugs | |
| Proton pump inhibitors (PPI) | Controversial: no difference vs poorer response rates in women Association between long-term PPI therapy and hip fractures is lower in women than men |
| Histamine 2 -receptor antagonists | No available data |
| Surgery | |
| Nissen fundoplication | Most studies have concluded no significant differences in efficacy In the US, women are more likely to undergo antireflux surgeries |
| Gastroparesis | |
| Dietary modifications | No available data |
| Medications | |
| Promotility agents | |
| Metoclopramide | Similar response rates to oral, but women may respond better to intranasal formulations |
| Domperidone | No reported differences in efficacy |
| Erythromycin | No available data Associated with more cardiac arrhythmias in women than men |
| Cisapride | No available data |
| Antiemetics | No reported differences in efficacy Women were more likely to have side effects to metoclopramide |
| Neuromodulators/analgesics | No reported differences (although limited data) |
| Procedures | |
| Pyloric botulinum injections | Conflicting: men may have superior responses than women overall, but women may respond to larger doses than men. No differences in durability |
| Nasojejunal tube feeds | No available data |
| Gastric electrical stimulator | No reported differences in efficacy |
Effect of Female Hormonal Stages on Gastroesophageal Reflux Disease
The authors were unable to find any studies highlighting symptom variation across the menstrual cycle for women with GERD.
During pregnancy, 85% of women report heartburn. The incidence of GERD increases with each trimester: 8%, 40%, and 52% for the first, second, and third trimester, respectively. Following delivery, the incidence of GERD becomes greatly reduced or absent. Increasing maternal age, higher prepregnancy BMI, certain ethnic groups (ie, Caucasian, Native American), tobacco/coffee consumption, and prepregnancy upper GI complaints are associated with higher prevalence of heartburn during pregnancy. Of note, some pregnant women with symptoms of GERD have normal ambulatory esophageal pH testing.
The cause of GERD during pregnancy is likely multifactorial and can vary by trimester. Throughout pregnancy, the progressive increase in progesterone and estrogen can reduce LESPs and effective esophageal body peristalsis to help with the clearance of reflux contents. Later in pregnancy, the enlarging uterus compressing the stomach can increase intragastric pressures and cause a mass effect resulting in mechanical alterations of the LES such as loss of the intra-abdominal LES segment and/or shifting of supporting anatomic structures surrounding the LES (eg, diaphragm).
In a survey study by Infantino, postmenopausal women were 2.9 times more likely to have GERD symptoms than premenopausal women. This finding is somewhat inconsistent with 2 prior studies that found only a slight association between age and increased prevalence of GERD symptoms up until the ages of 55 to 69 years old, from which point the trend reversed. If progesterone and estrogen substantially contribute to the cause of GERD in women, one would expect the opposite: a decreased incidence of GERD in postmenopausal women. Other factors associated with aging likely contribute to this increased incidence of GERD with age, such as weight gain, fat redistribution, alcohol, smoking, medications, comorbidities, and so on. In the aforementioned study, women in the postmenopausal group were in fact heavier and consumed more alcohol.
However, the association between BMI and reflux symptoms seems to be stronger in premenopausal than postmenopausal women in the study by Nilsson and colleagues. This study also observed a dose-dependent increase in the risk of reflux symptoms for women on hormone replacement therapy (HRT), which was greater with increasing BMI. These findings support female hormones playing a role in the association between BMI and reflux symptoms.
Sex Differences in Other Esophageal Motor Disorders
In an Australian study by Andrews and colleagues, there was a higher prevalence of ineffective or reflux-related esophageal motility disorder in men than women (34% vs 23%, P = .01). In an American study by Tsuboi and colleagues, there was a higher prevalence of nutcracker esophagus in women than men (8.5% vs 4.6%, P <.001), while men had a higher prevalence of nonspecific esophageal motility disorders (13.7% vs 10.7%, P = .003). Sex otherwise has no effect on other esophageal motor disorder diagnoses: normal, achalasia, or diffuse esophageal spasms. In the former Australian study, women were more commonly referred to a specialist for evaluation of esophageal motor disorders.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
