Female predominance in gastroparesis

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.

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.