Sex-Dependent Modulation of Clinical Outcomes Following Laparoscopic Cholecystectomy

A patient's gender is a strong and significant predictor for substantial differences in clinical outcomes such as postoperative pain, analgesic use, and surgical complications (gangrenous gallbladder, empyema of the gallbladder, gallbladder perforation, and conversion to open surgery) following laparoscopic cholecystectomy (Bingener et al., 2002; Bingener et al., 2003; Uchiyama et al., 2006). Although females present for laparoscopic cholecystectomy more frequently (76% of the cases); the prevalence of surgical complications during cholecystectomy is higher in men, most frequently because of inflammation or deterioration of the gallbladder (Bingener et al., 2002; Bingener et al., 2003; Stefanidis et al., 2006). Post-operatively, however, females report significantly greater pain scores and require larger amounts of analgesics (Uchiyama et al., 2006), suggesting that although surgeries are completed with fewer problems, females still report more post-operative pain. Sex-related differences in pain thresholds and tolerance to thermal, pressure, and electrical stimuli in experimental pain models indicate that pain differences are not solely due to psychosocial distinctions between the sexes (Riley et al., 1998).

There are multiple physiological differences between males and females; however, considerable evidence implicates estrogenic sex hormones as critical factors in sex-dependent differences in pain (see review by Fillingim and Ness, 2000). It is possible that estrogens alter inflammatory mediator profiles in the gallbladder, which subsequently increase sensitization of visceral neurons innervating the gallbladder, resulting in increased pain in females. The first portion of this study will extend the association of patient sex with clinical outcomes to determine whether circulating and/or local estrogen levels correlate with differences in peri-operative morbidity, including intra-operative complications, conversion to open cholecystectomy, postoperative pain, inadequate wound healing, intra-abdominal infection, disability and mortality.

Previous studies have demonstrated that the cytokines TNFalpha and IL-1beta alter the sensitivity of sensory neurons and increase nociception (Opree and Kress, 2000). To determine whether estrogen levels alter the profile of inflammatory mediators within the gallbladder and result in an increase in nociceptive thresholds in females, we will correlate circulating and/or local levels of estrogens with the amount of inflammatory mediators present within laparoscopically excised gallbladder biopsies. Patients who meet the inclusion criteria will be recruited from University Hospital in San Antonio. Inflammatory mediators, including the cytokines IL-1beta, TNFalpha, IL-8, IL-6, IL-10, and IL-12p70 will be assayed from interstitial fluid of biopsies from the fundus and infundibulum of the gallbladder. Biopsies will be classified according to clinical assessment prior to surgery to control for expected differences in inflammatory mediators in acute versus chronic cholecystitis.

The immediate effects of this research will be to clearly delineate whether estrogens are predictive of improved clinical outcomes following surgery and to determine whether these sex hormones correlate with altered production of inflammatory mediators in the gallbladder.