Gender Bias in Gastroparesis: Is Nitric Oxide the Answer?

Abstract

Accumulating evidence suggests that gender-related differences are prominent in gastric motility functions in both health and disease. Women are more susceptible to gastroparesis than men. Though the mechanism(s) involved are not fully understood, impairment of the nitrergic system is one of the main factors responsible for the disease. Uncoupling of neuronal nitric oxide synthase (nNOS) causes a decreased synthesis of NO leading to a reduction in smooth muscle relaxation. Tetrahydrobiopterin (BH4) (an essential cofactor for nNOS) is a key regulator of nNOS activity for stomach dysfunction and gastroparesis. In addition, BH4 has been shown to be a potent antioxidant and anti-inflammatory agent. Well established by results from our laboratory, a diminished intracellular (BH4:total biopterin) ratio in diabetic female rats significantly impairs nNOS activity and function. Recent research has been focused on BH4 biosynthesis and gastroparesis because reduced BH4 cofactor levels can alter the production of NO by nNOS. Researchers are now paying more attention to the possibility of using BH4 as a therapeutic strategy in gastroparesis. The purpose of this review is to provide an overview of the regulation and function of nNOS by sex hormones and BH4 and its potential role in the treatment of gastroparesis.

Estrogens and Gastroparesis: A Clinical Relevance

“…Finally, this may provide a misleading interpretation of the beneficial effects of these hormones on regulating gastric motility. In contrast, other studies have shown that, in general, gastric emptying is slower in young female rodents than age-matched male counterparts, and that estrogen may be the contributor for observed slower gastric emptying in both pregnant and non-pregnant rodents (reviewed in detail in [4]). Nevertheless, the above studies undoubtedly suggest that endogenous sex hormones may play an important role in gastric motility functions in females, and that a change in hormone levels and/or their receptor concentrations may drastically affect the stomach motility function that is seen in a diabetic or idiopathic setting [4].…”

“…Women, in particular the younger population with a mean age of 33-44 years, are more susceptible for gastroparesis than age-matched men [1][2][3]. Ovarian hormonal influence has been proposed as a major contributor to changes observed in gastric emptying in both health and disease states [4]. Most of our understanding for gastroparesis has come from animal studies focused on diabetic, hyperlipidemia, and oxidative stress-induced gastroparesis (reviewed in detail in [4]).…”

“…Ovarian hormonal influence has been proposed as a major contributor to changes observed in gastric emptying in both health and disease states [4]. Most of our understanding for gastroparesis has come from animal studies focused on diabetic, hyperlipidemia, and oxidative stress-induced gastroparesis (reviewed in detail in [4]). Most recently, Ravella et al [5] demonstrated that lack of sex hormones can lead to impaired nitrergic function leading to delayed gastric emptying.…”

“…Estrogen and progesterone have inhibitory effects on smooth muscle of the lower esophageal sphincter, pylorus, and small bowel muscle strips, resulting in decreased gastrointestinal contractility [4,8]. Some studies suggest that gastric emptying is slower in females during the luteal phase of the menstrual cycle, when estrogen and progesterone levels are elevated, whereas others do not (reviewed in detail in [4]). Heitkemper et al [9] demonstrated that the exacerbation of symptoms during the luteal phase in patients with irritable bowel syndrome.…”

“…The role of nitric oxide has been well established in stomach motility functions [4]. nNOS is an inhibitory neurotransmitter and plays a critical role in stomach emptying.…”