Sex Differences in the Exocrine Pancreas and Associated Diseases

Abstract

Differences in pancreatic anatomy, size, and function exist in men and women. The anatomical differences could contribute to the increase in complications associated with pancreatic surgery in women. Although diagnostic criteria for pancreatitis are the same in men and women, major sex differences in etiology are reported. Alcohol and tobacco predominate in men, whereas idiopathic and obstructive etiologies predominate in women. Circulating levels of estrogens, progesterone, and androgens contribute significantly to overall health outcomes; premenopausal women have lower prevalence of cardiovascular and pancreatic diseases suggesting protective effects of estrogens, whereas androgens promote growth of normal and cancerous cells. Sex chromosomes and gonadal and nongonadal hormones together determine an individual’s sex, which is distinct from gender or gender identity. Human pancreatic disease etiology, outcomes, and sex-specific mechanisms are largely unknown. In rodents of both sexes, glucocorticoids and estrogens from the adrenal glands influence pancreatic secretion and acinar cell zymogen granule numbers. Lack of corticotropin-releasing factor receptor 2 function, a G protein–coupled receptor whose expression is regulated by both estrogens and glucocorticoids, causes sex-specific changes in pancreatic histopathology, zymogen granule numbers, and endoplasmic reticulum ultrastructure changes in acute pancreatitis model. Here, we review existing literature on sex differences in the normal exocrine pancreas and mechanisms that operate at homeostasis and diseased states in both sexes. Finally, we review pregnancy-related pancreatic diseases and discuss the effects of sex differences on proposed treatments in pancreatic disease.

Developmentally dynamic changes in DNA methylation in the human pancreas

“…As expected, the vast majority of these differences occurred at sites located on the X chromosome (n = 12,242 (94.5%), mean male-female difference = 0.18 (SD = 0.12), range of male-female differences = 0.69 – 0.01), although a notable proportion were autosomal (n = 646 (4.99%), mean male-female difference = 0.048 (SD = 0.037), range of male-female differences = 0.30 – 0.009) ( Supplementary Table 11 ). This may indicate sex-specific differences in gene regulation in the developing pancreas and is an interesting observation given evidence for male-female differences in pancreatic size and function (Wang et al, 2021, Yong et al, 2022). The top-ranked autosomal DMP between males and females was cg06513015 (difference in mean DNA methylation = 0.27, P = 2.34 × 10 −78 ) which is annotated to the promoter regions of the ERV3-1 gene; of note this site has previously been shown to have significantly higher DNA methylation in newborn females compared to males (Hu et al, 2023, Santos et al, 2023) ( Supplementary Figure 6 ).…”

JMJD3 Is Required for Acute Pancreatitis and Pancreatitis-Associated Lung Injury

“…It is reported that Cae is a cholecystokininpancreozymin analog and is used to successfully cause AP in male mice, which belongs to a hormone-induced model (54). In addition, the effects of estrogens in female mice in the setting of AP are complex and vary with sex (55). To avoid the influence of estrogens in female mice, male mice are favorably used to establish the AP model compared with the female ones (56).…”

Gender-related differentially expressed genes in pancreatic cancer: possible culprits or accomplices?

“…The relatively higher incidence rates of PC in males have been shown in certain regions, for example, in 2020 in Eastern and Western Europe (with an age-standardized incidence rate per 100,000 of 9.9 for males and 5.6 for females and 9.8 for males and 7.4 for females, respectively), Northern America, Southern Europe, and Northern Europe, among others ( Sung et al, 2021 ). One possible reason, aside from females’ less exposure to PC risk factors ( Mario et al, 2018 ) including the growing rates of obesity, diabetes, and alcohol consumption, might be the sex effect on PC development and progression both in humans and rodent animal models ( Longnecker and Sumi, 1990 ; Wang et al, 2021 ). In fact, glucocorticoids and hormones have shown to affect the physiology of pancreas.…”

“…In fact, glucocorticoids and hormones have shown to affect the physiology of pancreas. Accordingly, in the PC rat models which were treated with azaserine, estrogens could play a protective role, while androgens possibly facilitate the development of PC ( Wang et al, 2021 ). In line with that, evidence also points to the existence of an association between PC and sex hormone signaling in humans.…”

“…In line with that, evidence also points to the existence of an association between PC and sex hormone signaling in humans. In this regards, several anti-androgen drugs were tested in PC models, and their potential antitumor effect was demonstrated ( Schweizer and Yu, 2017 ; Wang et al, 2021 ). However, the results of the related clinical trials have shown conflicting results ( Schweizer and Yu, 2017 ).…”