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Sex Differences in the Exocrine Pancreas and Associated Diseases

2021; Elsevier BV; Volume: 12; Issue: 2 Linguagem: Inglês

10.1016/j.jcmgh.2021.04.005

2352-345X

Melinda Wang, Fred S. Gorelick, Aditi Bhargava,

Neuroendocrine Tumor Research Advances

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. 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. SummaryHere, we review existing literature on sex differences in normal and diseased exocrine pancreas. We discuss known factors that influences sex-biased (patho)physiological processes and general principles to consider while addressing sex differences in the pancreas. Here, we review existing literature on sex differences in normal and diseased exocrine pancreas. We discuss known factors that influences sex-biased (patho)physiological processes and general principles to consider while addressing sex differences in the pancreas. There is growing recognition that sex-biased factors can modify both physiologic and disease responses involving the gastrointestinal tract. As a reflection of the importance of this concept, the National Institutes of Health announced a policy to include "sex as a biological variable" that requires investigators to explicitly consider the impact of sex in research design and data interpretation. Sex chromosome or autosome genes, sex hormones, and the environment together determine an individual's sex. This is distinct from gender or gender identity, which is an individual's perception of self and by society as male, female, or both. Thus, only humans have gender, as we recognize it, whereas both humans and animals have sex. Although sex-dependent differences in pancreatic disease etiology and outcomes are recognized, the sex-specific mechanisms that affect these responses are largely unknown. Most mechanistic studies focused on the effects of estrogen and glucocorticoid metabolites on acinar cell function, whereas data on the roles of androgens and progesterone and their respective metabolites is nonexistent. Side-by-side comparisons of mechanistic studies or disease outcomes in animal models inclusive of both sexes are rarely performed. Similarly, few clinical studies that have considered sex as a variable in analysis of pancreatic disease outcomes, as highlighted in this review. This emphasizes the need for a more comprehensive and deliberate inclusion of sex as a variable in clinical diagnosis, study designs, and data analyses of pancreatic diseases. Sex-dependent differences are first reviewed in the context of the normal exocrine pancreas. Next, we delineate proposed mechanisms driving sex differences in exocrine pancreas disease states, focusing on hormonal signaling pathways. Finally, we summarize the reported effects of sex steroid hormones and their targets on biologic responses and (patho)physiological outcomes. Most studies addressing sex differences in (patho)physiological outcomes in the pancreas have focused on the role of circulating levels of sex steroid hormones, mainly estradiol and corticosterone; thus, the data on understanding the role of different sex steroids on pancreatic acinar cells are limited. The perception of estrogens/progesterone as female and testosterone as male hormones is misleading. It is important to remember that both sexes and all genders have all classes of steroid hormones including estrogens, progesterone, and androgens, albeit at different levels that vary depending on the age in both humans and rodents.1Becker M. Hesse V. Minipuberty: Why does it happen?.Horm Res Paediatr. 2020; 93: 76-84Crossref PubMed Scopus (3) Google Scholar,2Nilsson M.E. Vandenput L. Tivesten A. Norlén A.-K. Lagerquist M.K. Windahl S.H. Börjesson A.E. Farman H.H. Poutanen M. Benrick A. Maliqueo M. Stener-Victorin E. Ryberg H. Ohlsson C. Measurement of a comprehensive sex steroid profile in rodent serum by high-sensitive gas chromatography-tandem mass spectrometry.Endocrinology. 2015; 156: 2492-2502Crossref PubMed Scopus (144) Google Scholar Sex hormone synthesis and secretion is regulated by the hypothalamic-pituitary-gonadal (HPG) axis in which gonadotropin-releasing hormone secreted from the hypothalamus into the portal circulation reaches the anterior pituitary, ultimately leading to the secretion of follicle-stimulating hormone and luteinizing hormone. Pulsatile release of these hormones supports continuous steroidogenesis and sperm production in males3Morris J.A. Jordan C.L. Breedlove S.M. Sexual differentiation of the vertebrate nervous system.Nat Neurosci. 2004; 7: 1034-1039Crossref PubMed Scopus (468) Google Scholar and ova development, ovulation, and stimulation of estradiol and progesterone from the ovaries in females.1Becker M. Hesse V. Minipuberty: Why does it happen?.Horm Res Paediatr. 2020; 93: 76-84Crossref PubMed Scopus (3) Google Scholar Gonads, adrenals, brain, and the placenta are the primary steroidogenic tissues that express P450scc (CYP11A1) to initiate steroidogenesis by converting cholesterol to pregnenolone, the precursor for all steroid hormones.4Mellon S.H. Griffin L.D. Neurosteroids: biochemistry and clinical significance.Trends Endocrinol Metab. 2002; 13: 35-43Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar,5Miller W.L. Bose H.S. Early steps in steroidogenesis: intracellular cholesterol trafficking.J Lipid Res. 2011; 52: 2111-2135Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar In addition, many nonsteroidogenic tissues (liver, kidney, adipose fat, breast, heart) express other steroidogenic enzymes that modify steroid precursors taken up from the circulation.6Arlotto M.P. Trant J.M. Estabrook R.W. Measurement of steroid hydroxylation reactions by high-performance liquid chromatography as indicator of P450 identity and function.Methods Enzymol. 1991; 206: 454-462Crossref PubMed Scopus (0) Google Scholar, 7Charni-Natan M. Aloni-Grinstein R. Osher E. Rotter V. Liver and steroid hormones-can a touch of p53 make a difference?.Front Endocrinol (Lausanne). 2019; 10: 374Crossref PubMed Scopus (9) Google Scholar, 8Deslypere J.P. Verdonck L. Vermeulen A. Fat tissue: a steroid reservoir and site of steroid metabolism.J Clin Endocrinol Metab. 1985; 61: 564-570Crossref PubMed Google Scholar Adipose tissue, particularly in postmenopausal women and older men, can contribute significantly to the systemic bioactive circulation of estradiol.9Nelson L.R. Bulun S.E. Estrogen production and action.J Am Acad Dermatol. 2001; 45: S116-S124Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar Circulating sex steroid hormones (endocrine actions) or those secreted locally (paracrine or autocrine actions) bind their cognate receptors—estrogen receptors (ERα, Erβ) and G protein–coupled estrogen receptor 1 (GPER [also known as GPR30]), progesterone receptor (PR), and androgen receptors. With the exception of GPER, each is in the nuclear receptor family and these hormone-receptor complexes bind to specific promoter regions to regulate a range of transcriptional responses (Figure 1A).10Robles-Diaz G. Duarte-Rojo A. Pancreas: a sex steroid-dependent tissue.The Israel Med Assoc J. 2001; 3: 364-368PubMed Google Scholar The human and rodent pancreata are highly innervated and along with hormones (endocrine and gut), neural inputs regulate secretion from the exocrine pancreas. Included are peptide hormones, such as gonadotropins and their associated cognate hormone receptors, which differ in localization throughout the body. For example, gonadotropin-releasing hormone is found in hypothalamic and peripheral tissues, such as the placenta, gonads, mammary glands, and the pancreas.11Wang L. Xie L.P. Huang W.Q. Yao B. Pu R.L. Zhang R.Q. Presence of gonadotropin-releasing hormone (GnRH) and its mRNA in rat pancreas.Mol Cell Endocrinol. 2001; 172: 185-191Crossref PubMed Scopus (0) Google Scholar Normal human pancreatic tissue expresses ERα, ERβ, GPER, PR, and androgen receptors.10Robles-Diaz G. Duarte-Rojo A. Pancreas: a sex steroid-dependent tissue.The Israel Med Assoc J. 2001; 3: 364-368PubMed Google Scholar Several other peptide hormone/receptor systems are expressed in the mammalian pancreas, but the precise role and function of many of these systems remains unclear. The HPG axis and sex steroid hormones also interact with the components of the stress hypothalamic-pituitary-adrenal (HPA) axis, the mediator of stress responses, which can impact gastrointestinal disease processes.12Peyrot C. Brouillard A. Morand-Beaulieu S. Marin M.F. A review on how stress modulates fear conditioning: let's not forget the role of sex and sex hormones.Behav Res Ther. 2020; 129: 103615Crossref PubMed Scopus (2) Google Scholar For example, although best known for their role in mediating "flight or fight" stress responses through the HPA axis, peptide hormones of the corticotropin-releasing-factor (CRF) system, including CRF, 3 urocortins (UCN1–3), and their 2 G protein–coupled receptors, CRF type 1 (CRF1) and type 2 (CRF2), are expressed in both the exocrine and the endocrine pancreas, where they regulate acinar cell secretion, organelle stress, and glucose homeostasis.13Kubat E. Mahajan S. Liao M. Ackerman L. Ohara P.T. Grady E.F. Bhargava A. Corticotropin-releasing factor receptor 2 mediates sex-specific cellular stress responses.Mol Med. 2013; 19: 212-222Crossref PubMed Scopus (9) Google Scholar, 14Vuppaladhadiam L. Ehsan C. Akkati M. Bhargava A. Corticotropin-releasing factor family: a stress hormone-receptor system's emerging role in mediating sex-specific signaling.Cells. 2020; 9: 839Crossref Scopus (2) Google Scholar, 15Yuan J. Hasdemir B. Tan T. Chheda C. Rivier J. Pandol S.J. Bhagava A. Protective effects of urocortin 2 against caerulein-induced acute pancreatitis.PLoS One. 2019; 14e0217065Crossref PubMed Scopus (1) Google Scholar, 16Li C. Chen P. Vaughan J. Lee K.F. Vale W. Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasis.Proc Natl Acad Sci U S A. 2007; 104: 4206-4211Crossref PubMed Scopus (0) Google Scholar, 17Chen A. Brar B. Choi C.S. Rousso D. Vaughan J. Kuperman Y. Kim S.N. Donaldson C. Smith S.M. Jamieson P. Li C. Nagy T.R. Shulman G.I. Lee K.-F. Vale W. Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle.Proc Natl Acad Sci U S A. 2006; 103: 16580-16585Crossref PubMed Scopus (0) Google Scholar, 18Paruthiyil S. Hagiwara S.I. Kundassery K. Bhargava A. Sexually dimorphic metabolic responses mediated by CRF2 receptor during nutritional stress in mice.Biol Sex Differ. 2018; 9: 49Crossref PubMed Scopus (7) Google Scholar CRF, UCN1-3, and CRF receptors, are widely distributed, including in the gastrointestinal (GI) system,19Chang J. Hoy J.J. Idumalla P.S. Clifton M.S. Pecoraro N.C. Bhargava A. Urocortin2 expression in the rat gastrointestinal tract under basal conditions and in chemical colitis.Peptides. 2007; 28: 1453-1460Crossref PubMed Scopus (0) Google Scholar, 20D'Costa S. Ayyadurai S. Gibson A.J. Mackey E. Rajput M. Sommerville L.J. Wilson N. Li Y. Kubat E. Kumar A. Subramanian H. Bhargava A. Moeser A.J. Mast cell CRF2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability.J Allergy Clin Immunol. 2019; 143: 1865-1877.e4Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 21Hasdemir B. Mhaske P. Paruthiyil S. Garnett E.A. Heyman M.B. Matloubian M. 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On the one hand, CRF and UCN1 bind to CRF1 but only hypothalamic CRF, not UCN1, stimulates ACTH synthesis and secretion from the anterior pituitary, which in turn stimulates the synthesis and release of glucocorticoids from the adrenal glands (cortisol in humans and corticosteroid in rodents). On the other hand, binding of UCN1-3 to CRF2, facilitates negative feedback to the HPA axis and recovery from the stress responses.24Neufeld-Cohen A. Tsoory M.M. Evans A.K. Getselter D. Gil S. Lowry C.A. Vale W.W. Chen A. A triple urocortin knockout mouse model reveals an essential role for urocortins in stress recovery.Proc Natl Acad Sci U S A. 2010; 107: 19020-19025Crossref PubMed Scopus (0) Google Scholar The expression and function of CRF family members at baseline and in various disease states in both sexes is reviewed elsewhere.14Vuppaladhadiam L. Ehsan C. Akkati M. Bhargava A. Corticotropin-releasing factor family: a stress hormone-receptor system's emerging role in mediating sex-specific signaling.Cells. 2020; 9: 839Crossref Scopus (2) Google Scholar No study has evaluated the levels of sex steroid hormones in the mammalian pancreas. The human pancreas is compact retroperitoneal organ and is located juxtaposed to greater curvature of the stomach and proximal duodenum. The exocrine pancreas secretes a bicarbonate-rich fluid and digestive enzymes in response to a meal; the major role of the endocrine pancreas is insulin-mediated glucose homeostasis. Differences in pancreatic anatomy, size, and function exist in men and women; from birth until <90 years of age, women consistently have average smaller pancreas volume (∼15%–25%) than age- and body mass index–matched men.25Saisho Y. Butler A.E. Meier J.J. Monchamp T. Allen-Auerbach M. Pizza R.A. Butler P.C. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes.Clin Anat. 2007; 20: 933-942Crossref PubMed Scopus (262) Google Scholar Women have a smaller pancreatic head and total volume than men but no difference in body or tail pancreatic volume (Figure 1B and C).26Syed A.B. Mahal R.S. Schumm L.P. Dachman A.H. Pancreas size and volume on computed tomography in normal adults.Pancreas. 2012; 41: 589-595Crossref PubMed Scopus (0) Google Scholar Smaller pancreatic volumes, with proportional reductions in the size of other anatomical structures such as duct diameter (Figure 1B and D), could contribute to the increase in complications associated with pancreatic surgery in women compared with men.25Saisho Y. Butler A.E. Meier J.J. Monchamp T. Allen-Auerbach M. Pizza R.A. Butler P.C. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes.Clin Anat. 2007; 20: 933-942Crossref PubMed Scopus (262) Google Scholar,27Taylor T.V. Rimmer S. Holt S. Jeacock J. Lucas S. Sex differences in gallstone pancreatitis.Ann Surg. 1991; 214: 667-670Crossref PubMed Google Scholar For example, 4 risk factors associated with pancreatic duct stent occlusion in chronic pancreatitis are (1) stent diameter, (2) long stent length, (3) female sex, and (4) pancreatic exocrine insufficiency requiring oral enzyme supplementation.28Farnbacher M.J. Radespiel-Tröger M. König M.D. Wehler M. Hahn E.G. Schneider H.T. Pancreatic endoprostheses in chronic pancreatitis: Criteria to predict stent occlusion.Gastrointest Endosc. 2006; 63: 60-66Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Female sex is also an independent predictor for both development of exocrine insufficiency and a pancreatic fistula after patients have undergone a distal pancreatectomy.29Elliott I.A. Epelboym I. Winner M. Allendorf J.D. Haigh P.I. Population-level incidence and predictors of surgically induced diabetes and exocrine insufficiency after partial pancreatic resection.Perm J. 2017; 21: 16-095PubMed Google Scholar,30Makni A. Rebai W. Daghfouss A. Ayadi S. Fterich F. Chebbi F. Ksantini R. Jouini M. Kacem M. Ben Safta Z. Risk factors associated with pancreatic fistula after distal pancreatectomy.Tunis Med. 2012; 90: 148-153PubMed Google Scholar Interestingly, male sex is associated with increased risk of pancreaticoduodenal artery aneurysms rupture regardless of size of aneurysm.31Orion K.C. Najafian A. Ehlert B.A. Malas M.B. Black 3rd, J.H. Abularrage C.J. Gender predicts rupture of pancreaticoduodenal artery aneurysms.Ann Vasc Surg. 2016; 36: 1-6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Thus, the increased risk for women over men of complications of endoscopic interventions and surgery is likely due in part to the reduced pancreatic duct diameter on average (Figure 1B and D). Women have greater pancreatic echogenicity by ultrasonography than men (ratios 1.52:1), whereas fat-to-parenchyma ratio is similar in both sexes until <39 years of age; thereafter, women have ∼20%–29% less ratio than men as fat mass remains largely constant in women, but increases in men with age.25Saisho Y. Butler A.E. Meier J.J. Monchamp T. Allen-Auerbach M. Pizza R.A. Butler P.C. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes.Clin Anat. 2007; 20: 933-942Crossref PubMed Scopus (262) Google Scholar Women are more likely to develop a normal pancreatic variant with less fatty involution of ventral pancreatic tissue during embryogenesis.32Coulier B. The hypoechoic ventral embryologic cephalic pancreas: a large clinical prospective study.J Belge Radiol. 1996; 79: 120-124PubMed Google Scholar Screening ultrasonography has shown that men have more subclinical morphological changes including main pancreatic duct dilation and age-dependent calcification, whereas women have more cystic lesions.33Ikeda M. Sato T. Morozumi A. Fujino M.A. Yoda Y. Ochiai M. Kobayashi K. Morphologic changes in the pancreas detected by screening ultrasonography in a mass survey, with special reference to main duct dilatation, cyst formation, and calcification.Pancreas. 1994; 9: 508-512Crossref PubMed Google Scholar Pancreatic biological sensitivity to secretin, as defined by an increase in serum immunoreactive cationic trypsinogen after secretin challenge, can vary by sex; male sex, smoking, and alcohol intake are significantly associated with increased pancreatic sensitivity to secretin.34Andriulli A. Masoero G. Amato A. Felder M. Benitti V. Dobrilla G. De La Pierre M. Verme G. Serum immunoreactive cationic trypsinogen response to secretin in normal subjects.Am J Gastroenterol. 1983; 78: 579-583PubMed Google Scholar,35Tiscornia O.M. Mingorance F.N.L. Repetti J.A. Bank S. Tiscornia-Wasserman P.G. Exocrine pancreas function - sex, age, estrogenic and cholinergic tone - preliminary clinical value of citrates "magic powder".Acta Gastroenterol Latinoamericana. 2019; 49: 324-330Google Scholar Among men and women over 45 years of age, women have lower exocrine pancreas sensitivity to secretin and lower concentrations of bicarbonate in pancreatic juice; this is reversed with short-term estradiol (valerianate) administration in menopausal women.35Tiscornia O.M. Mingorance F.N.L. Repetti J.A. Bank S. Tiscornia-Wasserman P.G. Exocrine pancreas function - sex, age, estrogenic and cholinergic tone - preliminary clinical value of citrates "magic powder".Acta Gastroenterol Latinoamericana. 2019; 49: 324-330Google Scholar,36Tiscornia O.M. Cresta M.A. Celener D. de Lehmann E.S. Tumilasci O. Scacchi P. Dreiling D.A. Estrogen effects on basal bile-pancreatic secretion and the exocrine-endocrine pancreatic gland in the rat.Mt Sinai J Med. 1986; 53: 462-469PubMed Google Scholar These findings suggest that estradiol can enhance the efficiency of pancreatic bicarbonate secretion concentration and output volume. Mouse and rat pancreas are compact in the splenic side but diffusely dispersed in the mesentery on the duodenal side37Tsuchitani M. Sato J. Kokoshima H. A comparison of the anatomical structure of the pancreas in experimental animals.J Toxicol Pathol. 2016; 29: 147-154Crossref PubMed Scopus (25) Google Scholar; rats but not mice lack a gall bladder. Estradiol administration in male rats increases acinar cell enzyme content but decreased amylase secretion in vivo.38Tangoku A. Doi R. Chowdhury P. Blevins G.T. Pasley J.N. Rayford P.L. Exogenous administration of estradiol and cholecystokinin alters exocrine pancreatic function in rats.Int J Pancreatol. 1993; 13: 81-86PubMed Google Scholar While gonadectomy has no perceptible effect on acinar cell morphology or zymogen granule numbers, when combined with adrenalectomy it results in marked reduction in zymogen granule numbers and morphology.39Beaudoin A.R. Grondin G. St-jean P. Vachereau A. Cabana C. Grossman A. Steroids and the secretory function of the exocrine pancreas.Endocrinology. 1986; 119: 2106-2117Crossref PubMed Google Scholar,40Grossman A. Boctor A.M. Band P. Lane B. 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Marked differences in immunocytological localization of [3H]estradiol-binding protein in rat pancreatic acinar tumor cells compared with normal acinar cells.Endocrinology. 1991; 128: 1617-1622Crossref PubMed Scopus (5) Google Scholar; these effects of estrogen are distinct from the actions mediated by ER. In ovariectomized and adrenalectomized female rats, pancreatic acini show wider intralobular and interlobular spaces and decreased acinar lumen size that does not resolve with estradiol treatment.42Beaudoin A.R. St-Jean P. Proulx J. Grondin G. Influence of steroids on the exocrine pancreas: Presence of laminated bodies in the acinar lumen following castration and adrenalectomy.Pancreas. 1989; 4: 219-227Crossref PubMed Scopus (8) Google Scholar In castrated and adrenalectomized male rats, acinar cells show both increased peri- and interlobular spaces that are normalized with estradiol treatment. Swollen Golgi apparatus and increased numbers of condensing vacuoles with the Golgi and zymogen granules are reversed with estradiol treatment.39Beaudoin A.R. Grondin G. St-jean P. Vachereau A. Cabana C. Grossman A. Steroids and the secretory function of the exocrine pancreas.Endocrinology. 1986; 119: 2106-2117Crossref PubMed Google Scholar Glucocorticoids and progesterone, but not estrogen treatment, in the AR42J rat pancreatic acinar–derived tumor cell line increase number of secretory granules within cells and amylase content.43Logsdon C.D. Moessner J. Williams J.A. Goldfine I.D. Glucocorticoids increase amylase mRNA levels, secretory organelles, and secretion in pancreatic acinar AR42J cells.J Cell Biol. 1985; 100: 1200-1208Crossref PubMed Google Scholar Estradiol administration to isolated rat acinar cells doubled intracellular amylase and trypsin contents compared with unstimulated controls as a result of increase in translation of these secretory proteins, but unlike cholecystokinin, did not affect secretion.44Hilgendorf I. Gellersen O. Emmrich J. Mikkat U. Rohwedel J. Krammer H.J. Müller P.K. Kruse C. Estradiol has a direct impact on the exocrine pancreas as demonstrated by enzyme and vigilin expression.Pancreatology. 2001; 1: 24-29Crossref PubMed Scopus (0) Google Scholar In male rats with obstructive jaundice, plasma estradiol and cholecystokinin levels were increased compared with controls and both levels were positively associated with pancreatic weight and plasma bilirubin levels.45Tangoku A. Doi R. Chowdhury P. Blevins Jr., G.T. Pasley J.N. Chang L.W. Rayford P.L. Humoral factors that induce alterations of the pancreas in rats with obstructive jaundice.Pancreas. 1993; 8: 103-108Crossref PubMed Google Scholar These findings suggest that both glucocorticoids and estrogens from the adrenals, rather than from the gonads, exert influence on pancreatic secretory apparatus.41Beaudoin A.R. Grondin G. St Jean P. Pettengill O. Longnecker D.S. Grossman A. Marked differences in immunocytological localization of [3H]estradiol-binding protein in rat pancreatic acinar tumor cells compared with normal acinar cells.Endocrinology. 1991; 128: 1617-1622Crossref PubMed Scopus (5) Google Scholar Exocrine pancreas function is only partially reversed by estradiol; steroid hormones exert their effects by acting directly on pancreatic acini, although downstream target genes and mechanisms are largely unknown. Few studies have considered sex as a biological variable in clinical outcomes in health or disease; instead, sex is accounted for as a confounder, thereby resulting in paucity of data in this area. Prominent sex-dependent differences in the features, including the impact of acute pancreatitis (AP) risk factors are described. In Chinese patients, higher mean waist circumference is associated with risk of AP, and mean waist circumference is higher in men than in women; smoking, alcohol consumption, abdominal adiposity, and diabetes were other factors that contributed to sex differences in increased AP risk.46Pang Y. Kartsonaki C. Turnbull I. Guo Y. Yang L. Bian Z. Chen Y. Millwood I.Y. Bragg F. Gong W. Xu Q. Kang Q. Chen J. Li L. Holmes M.V. Chen Z. Metabolic and lifestyle risk factors for acute pancreatitis in Chinese adults: a prospective cohort study of 0.5 million people.PLoS Medicine. 2018; 15e1002618Crossref PubMed Scopus (12) Google Scholar Similarly, in Danish patients, the incidence of AP is higher in men than in women.47Spanier B. Bruno M.J. Dijkgraaf M.G. Incidence and mortality of acute and chronic pancreatitis in the Netherlands: a nationwide record-linked cohort study for the years 1995–2005.World J Gastroenterol. 2013; 19: 3018-3026Crossref PubMed Scopus (70) Google Scholar These factors (smoking, alcohol, abdominal obesity, and diabetes) appear to account for the overall increased risk of developing AP in males worldw