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Tseng YT, Chen II, Wang CH. Association of Hormone Replacement Therapy with Inflammatory Bowel Disease Risk in Women with Menopausal Disorders: A Population-Based Retrospective Cohort Study. Healthcare (Basel) 2025; 13:578. [PMID: 40077140 PMCID: PMC11899444 DOI: 10.3390/healthcare13050578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/01/2025] [Accepted: 03/05/2025] [Indexed: 03/14/2025] Open
Abstract
Background: The long-term effects of hormone replacement therapy (HRT) on inflammatory bowel disease (IBD) remain unclear, necessitating further investigations of the association between HRT and the development of ulcerative colitis and Crohn's disease in postmenopausal women. Methods: This retrospective cohort study utilized Taiwan's National Health Insurance claims (2001-2018) to identify postmenopausal women aged ≥ 50 years with HRT use. A one-year washout period was applied before the index date to ensure new HRT users. To address the immortal time bias, follow-up for HRT users began at HRT initiation. The non-HRT group was selected by 1:1 propensity score matching. Cox proportional hazards models with adjustments for comorbidities and medications were used to estimate hazard ratios. Results: A total of 10,126 postmenopausal women (5063 per group) were included. During a mean follow-up of 11.1 years, the incidence rates of ulcerative colitis were 0.14 and 0.11 per 1000 person-years in the HRT and non-HRT groups, respectively. The adjusted hazard ratios were 1.33 (95% CI, 0.46-3.83; p = 0.600) for ulcerative colitis and 0.72 (95% CI, 0.45-1.16; p = 0.177) for Crohn's disease. Conclusions: This longitudinal study suggests that HRT use is not significantly associated with the risk of IBD among postmenopausal women. These findings indicate that IBD risk may not need to be a primary concern when considering HRT in this population.
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Affiliation(s)
- Yuan-Tsung Tseng
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan;
- Department of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan City 701, Taiwan
| | - I-I Chen
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), No. 670, Chongde Road, East District, Tainan City 701, Taiwan;
| | - Chun-Hsiang Wang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), No. 670, Chongde Road, East District, Tainan City 701, Taiwan;
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Li P, Chen Y, Xiang Y, Guo R, Li X, Liu J, Zhou Y, Fu X. 17β-estradiol promotes myeloid-derived suppressor cells functions and alleviates inflammatory bowel disease by activation of Stat3 and NF-κB signalings. J Steroid Biochem Mol Biol 2024; 242:106540. [PMID: 38719162 DOI: 10.1016/j.jsbmb.2024.106540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 04/26/2024] [Accepted: 05/01/2024] [Indexed: 06/16/2024]
Abstract
Inflammatory bowel disease (IBD) describes a group of clinically common autoimmune diseases characterized by chronic intestinal inflammation, with gender differences in prevalence. Estrogen has been previously shown to exert anti-inflammatory action in IBD development, however, the mechanisms remain obscure. Recent research has revealed that myeloid-derived suppressor cells (MDSCs) play a protective role in IBD pathogenesis. To investigate the molecular mechanisms of estrogen steroid 17β-estradiol (E2) in IBD progression, we established IBD mouse models (DNB-induced) with or without prior ovariectomy (OVX) and E2 implantation. We found that OVX led to worse IBD symptoms and reduced MDSCs frequency, whereas E2 significantly alleviated these effects in vivo. Moreover, in vitro experiments showed that E2 promoted the proliferation and immunosuppressive function of MDSCs through phosphorylation of Stat3 and p65. Mechanistically, E2-mediated Stat3/p65 phosphorylation depends on the interaction between HOTAIR, a long non-coding RNA that are well-known in MDSCs proliferation, and Stat3/p65 respectively. In conclusion, our study revealed that E2 promotes the expansion and immunosuppressive function of MDSCs, and thus diminished the occurrence and development of IBD.
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Affiliation(s)
- Ping Li
- Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China; Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, 511518, P.R. China
| | - Yiwen Chen
- Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Yixiao Xiang
- Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Ruixin Guo
- Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Xiaosa Li
- Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China
| | - Junxiu Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
| | - Yuting Zhou
- Department of Biotechnology, School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China.
| | - Xiaodong Fu
- Key Laboratory of Cardiovascular Diseases, Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, P.R. China; Affiliated Qingyuan Hospital, The Sixth Clinical Medical School, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, 511518, P.R. China; Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China.
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Pan J, Jiang W, Xin L, Wu J, Zhu S, Liu Z, Shen Z. The Potential Role of Female Sex Hormones in Patients With Inflammatory Bowel Disease: A 2-Sample Mendelian Randomization Study. Clin Transl Gastroenterol 2024; 15:e00748. [PMID: 38994837 PMCID: PMC11346901 DOI: 10.14309/ctg.0000000000000748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024] Open
Abstract
INTRODUCTION An association between female sex hormones and inflammatory bowel disease (IBD) has been reported in epidemiological studies. However, a solid causal relationship has not been established. Therefore, we performed a 2-sample Mendelian randomization (MR) study to explore the causal association between genetically predicted female sex hormone exposure, especially estrogen, and IBD. METHODS Genetic variants for female sex hormone exposure (ovulatory function, reproductive function, oral contraceptive pills, and hormone replacement therapy) were obtained from genome-wide association studies. Summary statistics for IBD were derived from the International Inflammatory Bowel Disease Genetics Consortium. We applied inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods in this MR study. Heterogeneity, horizontal pleiotropy, and sensitivity analyses were conducted to confirm the accuracy and robustness of our results. RESULTS Our study found that genetically predicted age at menarche was associated with an increased risk of Crohn's disease (odds ratio [OR] IVW 1.235, 95% confidence interval [CI] 1.028-1.484, P = 0.024), genetically predicted age of the last used hormone replacement therapy was associated with an increased risk of ulcerative colitis (OR WM 1.636, 95% CI 1.011-2.648, P = 0.045), and genetically predicted number of live births was related to a decreased risk of Crohn's disease (OR IVW 0.583, 95% CI 0.373-0.912, P = 0.018). DISCUSSION This study provided evidence for a link between female sex hormone exposure, especially estrogen, and IBD. Further investigations are needed to explore the causal effect of estrogen on IBD activity and the underlying mechanism of estrogen in IBD.
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Affiliation(s)
- Jiaqi Pan
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wenxi Jiang
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Linying Xin
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jiali Wu
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shefeng Zhu
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhaoxue Liu
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhe Shen
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Awasthi BP, Chaudhary P, Lim D, Yadav K, Lee IH, Banskota S, Chaudhary CL, Karmacharya U, Lee J, Im SM, Nam Y, Eun JW, Lee S, Lee JM, Kim ES, Ryou C, Kim TH, Park HD, Kim JA, Nam TG, Jeong BS. G Protein-Coupled Estrogen Receptor-Mediated Anti-Inflammatory and Mucosal Healing Activity of a Trimethylpyridinol Analogue in Inflammatory Bowel Disease. J Med Chem 2024; 67:10601-10621. [PMID: 38896548 DOI: 10.1021/acs.jmedchem.3c02458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Inflammatory bowel disease (IBD) is characterized by abnormal immune responses, including elevated proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the gastrointestinal (GI) tract. This study presents the synthesis and anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues, which exhibit dual inhibition of TNFα- and IL-6-induced inflammation. Analysis using in silico methods, including 3D shape-based target identification, modeling, and docking, identified G protein-coupled estrogen receptor 1 (GPER) as the molecular target for the most effective analogue, 6-26, which exhibits remarkable efficacy in ameliorating inflammation and restoring colonic mucosal integrity. This was further validated by surface plasmon resonance (SPR) assay results, which showed direct binding to GPER, and by the results showing that GPER knockdown abolished the inhibitory effects of 6-26 on TNFα and IL-6 actions. Notably, 6-26 displayed no cytotoxicity, unlike G1 and G15, a well-known GPER agonist and an antagonist, respectively, which induced necroptosis independently of GPER. These findings suggest that the GPER-selective compound 6-26 holds promise as a therapeutic candidate for IBD.
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Affiliation(s)
- Bhuwan Prasad Awasthi
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Prakash Chaudhary
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Dongchul Lim
- Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea
| | - Kiran Yadav
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Iyn-Hyang Lee
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Suhrid Banskota
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Chhabi Lal Chaudhary
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Ujjwala Karmacharya
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Jiwoo Lee
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - So Myoung Im
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - YeonJu Nam
- Bio Industry Department, Gyeonggido Business & Science Accelerator, Suwon 16229, Republic of Korea
| | - Ji Won Eun
- Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Sungeun Lee
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Ji-Min Lee
- Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Chongsuk Ryou
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Tae Hun Kim
- Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea
| | - Hee Dong Park
- Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea
| | - Jung-Ae Kim
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Tae-Gyu Nam
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University ERICA, Ansan, Gyeonggi-do 15588, Republic of Korea
| | - Byeong-Seon Jeong
- College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea
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Zou F, Hu Y, Xu M, Wang S, Wu Z, Deng F. Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study. Front Endocrinol (Lausanne) 2024; 15:1272746. [PMID: 38660517 PMCID: PMC11039946 DOI: 10.3389/fendo.2024.1272746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 03/28/2024] [Indexed: 04/26/2024] Open
Abstract
Background Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear. Method Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation. Results E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046). Conclusion Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.
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Affiliation(s)
- Fei Zou
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Yaxian Hu
- Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengmeng Xu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Su Wang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Zengrong Wu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
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Freeman M, Lally L, Teigen L, Graziano E, Shivashankar R, Shmidt E. Hormone Replacement Therapy Is Associated with Disease Activity Improvement among Post-Menopausal Women with Inflammatory Bowel Disease. J Clin Med 2023; 13:88. [PMID: 38202098 PMCID: PMC10779540 DOI: 10.3390/jcm13010088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 11/25/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
(1) Background: There are limited data available to guide clinical decision-making regarding the effects of hormone replacement therapy (HRT) in post-menopausal women with inflammatory bowel disease (IBD). In this study, we sought to characterize a population of post-menopausal women with IBD and to determine the effects of HRT on their disease activity. (2) Methods: A multicenter, retrospective, case-control cohort study of post-menopausal women with IBD was conducted. The physician global assessment (PGA) score was used to quantify disease activity. To control for the effects of menopause, IBD patients who had not undergone HRT were used as controls. (3) Results: There was a significant reduction in the frequency of PGA scores ≥2 post HRT treatment (p < 0.01). HRT treatment was associated with a 5.6× increase in the odds of post-HRT PGA score improvement compared to controls (OR 5.6; 95% CL 1.6, 19.7) in our univariate logistic regression analysis. (4) Conclusion: Post-menopausal IBD women who underwent HRT therapy showed an improvement in their disease symptoms following HRT compared to post-menopausal women without HRT therapy, who showed no change.
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Affiliation(s)
- Morgan Freeman
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA; (M.F.); (L.T.); (E.G.)
| | - Lauren Lally
- Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA 19107, USA (R.S.)
| | - Levi Teigen
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA; (M.F.); (L.T.); (E.G.)
| | - Elliot Graziano
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA; (M.F.); (L.T.); (E.G.)
| | - Raina Shivashankar
- Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA 19107, USA (R.S.)
| | - Eugenia Shmidt
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA; (M.F.); (L.T.); (E.G.)
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Newman KL, Chedid VG, Boden EK. A Systematic Review of Inflammatory Bowel Disease Epidemiology and Health Outcomes in Sexual and Gender Minority Individuals. Gastroenterology 2023; 164:866-871. [PMID: 37087155 PMCID: PMC11268438 DOI: 10.1053/j.gastro.2022.11.048] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/14/2022] [Accepted: 11/02/2022] [Indexed: 04/24/2023]
Affiliation(s)
| | | | - Elisa K Boden
- Oregon Health & Science University, Portland, Oregon
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Newman KL, Chedid VG, Boden EK. A Systematic Review of Inflammatory Bowel Disease Epidemiology and Health Outcomes in Sexual and Gender Minority Individuals. Clin Gastroenterol Hepatol 2023; 21:1127-1133. [PMID: 37088515 PMCID: PMC11268437 DOI: 10.1016/j.cgh.2023.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Affiliation(s)
| | | | - Elisa K Boden
- Oregon Health & Science University, Portland, Oregon
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Hof T, Thimme R, Hasselblatt P. [Diversity in gastroenterology - A focus on inflammatory bowel diseases]. Dtsch Med Wochenschr 2023; 148:519-527. [PMID: 37094587 DOI: 10.1055/a-1892-4878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
Factors related to patient diversity may play a major role in the pathogenesis and clinical manifestation of intestinal and liver diseases and should be considered during diagnostic workup and therapeutic decisions. Here we discuss how diversity factors such as gender, ethnicity, age and socioeconomic parameters may affect the manifestation and disease course of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis). Consideration of such factors may help to pave the path towards personalized medicine approaches in clinical practice.
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Impact of Female Gender in Inflammatory Bowel Diseases: A Narrative Review. J Pers Med 2023; 13:jpm13020165. [PMID: 36836400 PMCID: PMC9958616 DOI: 10.3390/jpm13020165] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/05/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
Inflammatory bowel diseases show a gender bias, as reported for several other immune-mediated diseases. Female-specific differences influence disease presentation and activity, leading to a different progression between males and females. Women show a genetic predisposition to develop inflammatory bowel disease related to the X chromosome. Female hormone fluctuation influences gastrointestinal symptoms, pain perception, and the state of active disease at the time of conception could negatively affect the pregnancy. Women with inflammatory bowel disease report a worse quality of life, higher psychological distress, and reduced sexual activity than male patients. This narrative review aims to resume the current knowledge of female-related features in clinical manifestations, development, and therapy, as well as sexual and psychological implications related to inflammatory bowel disease. The final attempt is to provide gastroenterologists with a roadmap of female-specific differences, to improve patients' diagnosis, management, and treatment.
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Gao XY, Jin Y, Zhao J, Zhang YL, Wang HW, Zhou BH. Th17-Related Cytokines Involved in Fluoride-Induced Cecal and Rectal Barrier Damage of Ovariectomized Rats. Biol Trace Elem Res 2022:10.1007/s12011-022-03519-6. [PMID: 36538210 DOI: 10.1007/s12011-022-03519-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
To investigate fluoride (F)-induced intestine barrier damage and the role of estrogen deficiency in this progress, a rat model of estrogen deficiency was established through bilateral surgical removal of ovaries. The F exposure model was then continued by adding sodium fluoride (0, 25, 50, and 100 mg/L, calculated on a fluorine ion basis) to drinking water for 90 days. Afterward, intestinal mucosal structure, barrier function, and inflammatory cytokines were evaluated. The results showed that excessive F decreased the developmental parameters (crypt depth) of the cecum and rectum and inhibited the proliferation capacity of the intestinal epithelia, which are more obvious in the state of estrogen deficiency. The distribution of goblet cells and glycoproteins in the intestinal mucosa decreased with the increase in F concentration, and estrogen deficiency led to a further decline, especially in the rectum. Using the immunofluorescence method, the study showed that excessive F caused interleukin-17A (IL-17A) significantly decrease in the cecum and increase in the rectum. Meanwhile, F treatment remarkably upregulated the expression of intestinal IL-1β, IL-23, and IL-22, while the level of IL-6 was downregulated. In addition, estrogen deficiency increased IL-1β, IL-6, IL-23, and IL-22, but decreased IL-17A expression in the cecum and rectum. Collectively, F exposure damaged intestinal morphological structure, inhibited epithelial cell proliferation and mucus barrier function, and resulted in the disturbance of T helper (Th) 17 cell-related cytokines expression. Estrogen deficiency may further aggravate F-induced damage to the cecum and rectum.
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Affiliation(s)
- Xiao-Ying Gao
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Ye Jin
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Jing Zhao
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Yu-Ling Zhang
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Hong-Wei Wang
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China
| | - Bian-Hua Zhou
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, 471000, Henan, People's Republic of China.
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Mendoza N, Ramírez I, de la Viuda E, Coronado P, Baquedano L, Llaneza P, Nieto V, Otero B, Sánchez-Méndez S, de Frutos VÁ, Andraca L, Barriga P, Benítez Z, Bombas T, Cancelo MJ, Cano A, Branco CC, Correa M, Doval JL, Fasero M, Fiol G, Garello NC, Genazzani AR, Gómez AI, Gómez MÁ, González S, Goulis DG, Guinot M, Hernández LR, Herrero S, Iglesias E, Jurado AR, Lete I, Lubián D, Martínez M, Nieto A, Nieto L, Palacios S, Pedreira M, Pérez-Campos E, Plá MJ, Presa J, Quereda F, Ribes M, Romero P, Roca B, Sánchez-Capilla A, Sánchez-Borrego R, Santaballa A, Santamaría A, Simoncini T, Tinahones F, Calaf J. Eligibility criteria for Menopausal Hormone Therapy (MHT): a position statement from a consortium of scientific societies for the use of MHT in women with medical conditions. MHT Eligibility Criteria Group. Maturitas 2022; 166:65-85. [PMID: 36081216 DOI: 10.1016/j.maturitas.2022.08.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/21/2022] [Accepted: 08/17/2022] [Indexed: 11/26/2022]
Abstract
This project aims to develop eligibility criteria for menopausal hormone therapy (MHT). The tool should be similar to those already established for contraception A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by women with medical conditions based on the best available evidence. The project was developed in two phases. As a first step, we conducted 14 systematic reviews and 32 metanalyses on the safety of MHT (in nine areas: age, time of menopause onset, treatment duration, women with thrombotic risk, women with a personal history of cardiovascular disease, women with metabolic syndrome, women with gastrointestinal diseases, survivors of breast cancer or of other cancers, and women who smoke) and on the most relevant pharmacological interactions with MHT. These systematic reviews and metanalyses helped inform a structured process in which a panel of experts defined the eligibility criteria according to a specific framework, which facilitated the discussion and development process. To unify the proposal, the following eligibility criteria have been defined in accordance with the WHO international nomenclature for the different alternatives for MHT (category 1, no restriction on the use of MHT; category 2, the benefits outweigh the risks; category 3, the risks generally outweigh the benefits; category 4, MHT should not be used). Quality was classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias). When no direct evidence was identified, but plausibility, clinical experience or indirect evidence were available, "Expert opinion" was categorized. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, has been defined. This will provide health professionals with a powerful decision-making tool that can be used to manage menopausal symptoms.
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Affiliation(s)
- Nicolás Mendoza
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain.
| | - Isabel Ramírez
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | - Pluvio Coronado
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Laura Baquedano
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Plácido Llaneza
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Verónica Nieto
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Borja Otero
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | - Leire Andraca
- Sociedad Española de Farmacia Comunitaria (SEFAC), Spain
| | | | - Zully Benítez
- Federación Latino Americana de Sociedades de Climaterio y Menopausia (FLASCYM)
| | - Teresa Bombas
- Red Iberoamericana de Salud Sexual y Reproductiva (REDISSER)
| | | | - Antonio Cano
- European Menopause and Andropause Society (EMAS)
| | | | | | - José Luis Doval
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - María Fasero
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Gabriel Fiol
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Nestor C Garello
- Federación Latino-Americana de Sociedades de Obstetricia y Ginecología (FLASOG)
| | | | - Ana Isabel Gómez
- Sociedad Española de Senología y Patología Mamaria (SESPM), Spain
| | - Mª Ángeles Gómez
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Silvia González
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | | | - Sonia Herrero
- Sociedad Española de Trombosis y Hemostasia (SETH), Spain
| | - Eva Iglesias
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Ana Rosa Jurado
- Sociedad Española de Médicos de Atención Primaria (SEMERGEN), Spain
| | - Iñaki Lete
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Daniel Lubián
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | - Aníbal Nieto
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Laura Nieto
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | | | | | - Jesús Presa
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | - Miriam Ribes
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Pablo Romero
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | - Beatriz Roca
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
| | | | | | | | | | | | | | - Joaquín Calaf
- Asociación Española para el Estudio de la Menopausia (AEEM), Spain
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13
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Xu L, Huang G, Cong Y, Yu Y, Li Y. Sex-related Differences in Inflammatory Bowel Diseases: The Potential Role of Sex Hormones. Inflamm Bowel Dis 2022; 28:1766-1775. [PMID: 35486387 DOI: 10.1093/ibd/izac094] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract, is a global health care problem. Compelling evidence shows sex differences regarding the prevalence, pathophysiology, clinical presentation, and treatment outcome of IBD. Sex hormones, including estrogen, progesterone, and androgen, have been proposed to have a role in the pathogenesis of sexual dimorphism in IBD. Clinical and experimental data support the modulatory effects of sex hormones on various clinical characteristics of the disease, including intestinal barrier dysfunction and mucosal immune activation. Additionally, the potential role of sex hormones in the modulation of gut microbiota is attracting increasing attention. Here, we discuss the sex dimorphic disease profile and address the potential mechanisms involved in the sex-specific pathogenesis of IBD. Improved understanding of these sex differences in the clinic could improve the knowledge of patients with IBD with heterogeneous disease profiles.
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Affiliation(s)
- Leiqi Xu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Gang Huang
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.,Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Yanbo Yu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
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14
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Abstract
Inflammatory bowel diseases (IBD), including Crohn disease and ulcerative colitis, are chronic inflammatory conditions of the gastrointestinal tract. Individuals with IBD are at increased risk for several malignancies originating in the intestine, such as colorectal cancer, small bowel adenocarcinoma, intestinal lymphoma, and anal cancer. There are also several extraintestinal malignancies associated with IBD and IBD therapies, including cholangiocarcinoma, skin cancer, hematologic malignancies, genitourinary cancer, cervical cancer, and prostate cancer. The authors summarize the risk of cancer in patients with IBD, diagnosis and management of colorectal neoplasia in IBD, and management of patients with IBD and active or recent cancer.
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Affiliation(s)
- Adam S Faye
- Inflammatory Bowel Disease Center at NYU Langone Health, 305 East 33rd Street, Lower Level, New York, NY 10016, USA
| | - Ariela K Holmer
- Inflammatory Bowel Disease Center at NYU Langone Health, 305 East 33rd Street, Lower Level, New York, NY 10016, USA
| | - Jordan E Axelrad
- Inflammatory Bowel Disease Center at NYU Langone Health, 305 East 33rd Street, Lower Level, New York, NY 10016, USA.
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15
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Moktan VP, Daoud ND, Tremaine WJ, Loftus EV, Kane SV, Hochwald AP, Hodge DO, Hashash JG, Faubion SS, Farraye FA. A Cohort Study of the Age at Menopause in Female Patients With and Without Inflammatory Bowel Disease. CROHN'S & COLITIS 360 2022; 4:otac027. [PMID: 36045902 PMCID: PMC9421681 DOI: 10.1093/crocol/otac027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Indexed: 11/14/2022] Open
Abstract
Abstract
Background
Menopause, defined by the complete cessation of menstrual cycles for 12 consecutive months, may occur at a younger age in women who have concomitant immune dysregulation. Our aim was to determine whether women with inflammatory bowel disease (IBD) experience an earlier onset of menopause compared to women without IBD.
Methods
This was a retrospective cohort study using resources of the Rochester Epidemiology Project, a collaboration between clinics, hospitals, and medical facilities in Olmsted County, Minnesota. From these people, women who were diagnosed with IBD between 1970 and 2010 comprised the case cohort while the reference cohort included women with no diagnosis of IBD. Data including age, body mass index (BMI), ethnicity, smoking status, age at onset of menopause, and current use of hormone therapy were collected. Patients with history of hysterectomy or oophorectomy were excluded. Wilcoxon rank-sum test for numeric variables and Fisher’s exact test for categorical variables were used to analyze the data.
Results
A total of 171 women met criteria for inclusion (83 cases and 88 controls). Mean age of menopause in women with IBD was 50.0 years compared to 51.5 years in women with no IBD (P = .006). There was no difference in BMI of women with and without IBD (28.7 versus 28.2 kg m−2; P = .9), respectively. There were more former smokers (33.7%) and current (6%) smokers in the IBD group (P = .009) compared to the non-IBD group.
Conclusions
IBD is associated with an earlier onset of menopause. Although it is unclear if this mean difference of 1.5 years is clinically relevant, it is known that early menopause is associated with an increased risk of osteoporosis and cardiovascular disease. Further research on the possible mechanisms is needed.
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Affiliation(s)
- Varun P Moktan
- Division of Community Internal Medicine, Mayo Clinic , Jacksonville, Florida , USA
| | - Nader D Daoud
- Division of Gastroenterology and Hepatology, Mayo Clinic , Jacksonville, Florida , USA
| | - William J Tremaine
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, Minnesota , USA
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, Minnesota , USA
| | - Sunanda V Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, Minnesota , USA
| | - Alexander P Hochwald
- Department of Biomedical Statistics and Informatics, Mayo Clinic , Jacksonville, Florida , USA
| | - David O Hodge
- Department of Biomedical Statistics and Informatics, Mayo Clinic , Jacksonville, Florida , USA
| | - Jana G Hashash
- Division of Gastroenterology and Hepatology, Mayo Clinic , Jacksonville, Florida , USA
| | - Stephanie S Faubion
- Division of General Internal Medicine, Mayo Clinic , Jacksonville, Florida , USA
| | - Francis A Farraye
- Division of Gastroenterology and Hepatology, Mayo Clinic , Jacksonville, Florida , USA
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16
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Ananthakrishnan AN, Kaplan GG, Bernstein CN, Burke KE, Lochhead PJ, Sasson AN, Agrawal M, Tiong JHT, Steinberg J, Kruis W, Steinwurz F, Ahuja V, Ng SC, Rubin DT, Colombel JF, Gearry R. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus. Lancet Gastroenterol Hepatol 2022; 7:666-678. [PMID: 35487235 DOI: 10.1016/s2468-1253(22)00021-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 06/14/2023]
Abstract
Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.
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Affiliation(s)
- Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
| | - Gilaad G Kaplan
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, AB, Canada
| | - Charles N Bernstein
- Section of Gastroenterology, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Kristin E Burke
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Paul J Lochhead
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Alexa N Sasson
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Manasi Agrawal
- Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Clinical Medicine, Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Aalborg University, Copenhagen, Denmark
| | - Jimmy Ho Tuan Tiong
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Joshua Steinberg
- Department of Gastroenterology, Hepatology, and Nutrition, Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Wolfgang Kruis
- Department of Internal Medicine, University of Cologne, Cologne, Germany
| | - Flavio Steinwurz
- Department of Gastroenterology, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Vineet Ahuja
- Department of Gastroenterology & Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Siew C Ng
- Department of Medicine and Therapeutics, LKS Institute of Health Science and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - David T Rubin
- Department of Gastroenterology, Hepatology, and Nutrition, Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Jean-Frederic Colombel
- Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Richard Gearry
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
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17
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Armuzzi A, Bortoli A, Castiglione F, Contaldo A, Daperno M, D'Incà R, Labarile N, Mazzuoli S, Onali S, Milla M, Orlando A, Principi M, Pugliese D, Renna S, Rizzello F, Scribano ML, Todeschini A. Female reproductive health and inflammatory bowel disease: A practice-based review. Dig Liver Dis 2022; 54:19-29. [PMID: 34120858 DOI: 10.1016/j.dld.2021.05.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/08/2021] [Accepted: 05/16/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, occur worldwide and affect people of all ages, with a high impact on their quality of life. Sex differences in incidence and prevalence have been reported, and there are also gender-specific issues that physicians should recognize. For women, there are multiple, important concerns regarding issues of body image and sexuality, menstruation, contraception, fertility, pregnancy, breastfeeding and menopause. This practice-based review focuses on the main themes that run through the life of women with inflammatory bowel diseases from puberty to menopause. Gastroenterologists who specialize in inflammatory bowel diseases and other physicians who see female patients with inflammatory bowel diseases should provide support for these problems and offer adequate therapy to ensure that their patients achieve the same overall well-being and health as do women without inflammatory bowel diseases.
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Affiliation(s)
| | - Alessandro Armuzzi
- CEMAD - IBD Unit, Department of Medical and Surgical Sciences, A Gemelli University Hospital, Rome, Italy
| | | | - Fabiana Castiglione
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine Federico II of Naples, Naples, Italy
| | - Antonella Contaldo
- Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy
| | - Marco Daperno
- Gastroenterology and Endoscopic Unit, Umberto I Mauriziano Hospital, Turin, Italy
| | - Renata D'Incà
- Gastroenterology Unit, Padua University Hospital, Padua, Italy
| | - Nunzia Labarile
- Gastroenterology Unit, Ospedale Santissima Annunziata, Taranto, Italy
| | - Silvia Mazzuoli
- Gastroenterology and Artificial Nutrition Department, "Mons. Dimiccoli " Barletta, Italy
| | - Sara Onali
- Gastroenterology Unit, Department of Science and Public Health, University Hospital of Cagliari, Italy
| | - Monica Milla
- IBD Referral Center, Gastroenterology Clinic, Careggi University Hospital, Florence, Italy
| | - Ambrogio Orlando
- Inflammatory Bowel Disease Unit, A.O.O.R. Villa Sofia-Cervello, Palermo, Italy
| | - Mariabeatrice Principi
- Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy.
| | - Daniela Pugliese
- CEMAD - IBD Unit, Department of Medical and Surgical Sciences, A Gemelli University Hospital, Rome, Italy
| | - Sara Renna
- Inflammatory Bowel Disease Unit, A.O.O.R. Villa Sofia-Cervello, Palermo, Italy
| | - Fernando Rizzello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Alessia Todeschini
- Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy
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18
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Hamdeh S, Micic D, Hanauer S. Review article: drug-induced small bowel injury. Aliment Pharmacol Ther 2021; 54:1370-1388. [PMID: 34668591 DOI: 10.1111/apt.16642] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/05/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Drug-induced gastrointestinal injury has been increasingly reported, but its exact incidence is not known. The small and large intestines represent the most affected sites of injury, accounting for 20%-40% of all gastrointestinal side effects. AIM To provide an updated literature review detailing medications linked to the development of small bowel injury. METHODS We conducted a literature search on PubMed from its inception to May 1, 2021. We included English-language original studies, meta-analyses, systematic reviews, review articles and case reports. RESULTS Drug-induced enteropathy can range from asymptomatic histological changes resulting in a subtle, self-limited disease to a chronic inflammatory condition mimicking inflammatory bowel disease, or bowel perforation. Endoscopy can demonstrate erythema, mucosal friability, oedema, erosions, ulcers or strictures in severe cases. Histology may include mucosal erosions and ulcerations, focal active enteritis, villous atrophy, epithelial apoptosis or necrotising enteritis. A well-established association has been found with the use of nonsteroidal anti-inflammatory drugs, immunosuppressants, chemotherapeutic agents, antibiotics, immunotherapies, etanercept and olmesartan. Possible associations have been reported with other biologic agents, medications used for glycemic control, antihypertensives, cholinesterase inhibitors, potassium and iron supplements, with conflicting data regarding contraceptives/hormonal therapy and isotretinoin. CONCLUSION Physicians should be aware of the manifestations of drug-induced enteropathy as early recognition can lead to prompt discontinuation of the offending therapy and, therefore, a reduced risk of future complications.
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Affiliation(s)
- Shadi Hamdeh
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Motility, University of Kansas, Lawrence, KS, USA
| | - Dejan Micic
- Department of Internal Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA
| | - Stephen Hanauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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19
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Evaluation of Sex Hormone Levels in Patients with Pemphigus Vulgaris in Comparison to the Healthy Population. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9947706. [PMID: 34621900 PMCID: PMC8492234 DOI: 10.1155/2021/9947706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 07/21/2021] [Accepted: 09/13/2021] [Indexed: 11/17/2022]
Abstract
Materials and Methods This cross-sectional study was performed on patients with pemphigus vulgaris referred to Faghihi Hospital and Shiraz Dental Faculty in 2017-2018. The participants included 26 women with histopathologically confirmed pemphigus vulgaris and 26 healthy age-matched controls. The serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, progesterone, testosterone, prolactin, dehydroepiandrosterone (DHEA), and dihydrotestosterone (DHT) were evaluated in both groups. Independent t-test and two-way ANOVA were used for data analysis. Results The mean age of the patients was 49.88 ± 10.46 years and that of the control group was 49.92 ± 11.30 years. Unlike the case group, the DHEA serum level was significantly higher among nonmenopausal participants in the control group. Moreover, the levels of testosterone and DHEA were significantly lower in the case group in comparison to the control group (p = 0.015 and p = 0.026, respectively). Conclusion Considering the effects of age and menopause, the serum levels of testosterone and DHEA were significantly lower in the patients with pemphigus vulgaris than in the healthy controls. Hence, these hormones might have a role in the pathogenesis of pemphigus vulgaris.
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20
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Hamdeh S, Micic D, Hanauer S. Drug-Induced Colitis. Clin Gastroenterol Hepatol 2021; 19:1759-1779. [PMID: 32360808 DOI: 10.1016/j.cgh.2020.04.069] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/31/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
Drug-induced colitis encompasses a wide spectrum of colon disorders that can manifest microscopically or macroscopically. Patients present with new-onset colitis or exacerbations of inflammatory bowel diseases; in some cases, colitis resolves with discontinuation of medication. Mucosal injury can be focal or extensive, involving the entire colonic mucosa, and sometimes involves other parts of the gastrointestinal tract. It has been a challenge to determine the proportion of new-onset colitis caused by medication and there are few data on the overall prevalence. We review the drugs that have been linked with development of drug-induced colitis and strategies for physicians who believe their patients have this disorder-usually discontinuation of the drug believed to cause colitis and treatment with steroids or immune-modulating therapies. Physicians must be aware of medications that can cause colitis.
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Affiliation(s)
- Shadi Hamdeh
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Motility, University of Kansas, Kansas City, Kansas.
| | - Dejan Micic
- Department of Internal Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
| | - Stephen Hanauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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21
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Garrido-Gil P, Rodriguez-Perez AI, Lage L, Labandeira-Garcia JL. Estrogen Deficiency and Colonic Function: Surgical Menopause and Sex Differences in Angiotensin and Dopamine Receptor Interaction. J Gerontol A Biol Sci Med Sci 2021; 76:1533-1541. [PMID: 32991714 DOI: 10.1093/gerona/glaa244] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Indexed: 01/02/2025] Open
Abstract
The physiopathological mechanisms that regulate menopausal and sex differences in colonic transit, inflammatory processes, and efficacy of treatments have not been clarified. The dopaminergic system and renin-angiotensin system coexist in the gut and regulate different processes such as motility, absorption/secretion, and inflammation. We investigated the changes in expression of major angiotensin and dopamine receptors in the colon of male, female, and ovariectomized female mice. Possible interaction between both systems was investigated using male and female mice deficient (ko) for major angiotensin and dopamine receptors. In wild-type mice, colonic tissue from females showed lower angiotensin type 1/angiotensin type 2 ratio (an index of pro-inflammatory/anti-inflammatory renin-angiotensin system balance), lower dopamine D1 and D2 receptor expression, and lower levels of pro-inflammatory and pro-oxidative markers relative to males. Interestingly, ovariectomy increased the expression of pro-inflammatory angiotensin type 1 receptor expression and decreased anti-inflammatory angiotensin type 2 receptor expression, increased D1 and D2 receptor expression, and increased the levels of pro-inflammatory and pro-oxidative markers. Ovariectomy-induced changes were blocked by estrogen replacement. The present results suggest a mutual regulation between colonic angiotensin and dopamine receptors and sex differences in this mutual regulation. Estrogen regulates changes in both angiotensin and dopamine receptor expression, which may be involved in sex- and surgical menopause-related effects on gut motility, permeability, and vulnerability to inflammatory processes.
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Affiliation(s)
- Pablo Garrido-Gil
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ana I Rodriguez-Perez
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Lucia Lage
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Spain
| | - Jose L Labandeira-Garcia
- Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Spain
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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Estrogen receptor actions in colitis. Essays Biochem 2021; 65:1003-1013. [PMID: 34342357 DOI: 10.1042/ebc20210010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 02/08/2023]
Abstract
In recent years, researchers have demonstrated that estrogen and its receptors, aside from their role in regulating several biological functions, contribute to the development and progression/severity of inflammatory bowel diseases (IBDs). IBDs include both ulcerative colitis (UC) and Crohn's disease (CD). Epidemiological data indicate a clear difference in the incidence, severity, and complications of IBDs between sexes. Men present a higher risk of developing colitis than women and a higher risk of developing colorectal cancer, a common complication of this condition. However, fluctuations of estrogen levels have yielded inconsistent data, where oral contraceptives and hormone replacement therapy have been associated with an increased risk of IBDs in premenopausal women but significantly reduce disease activity after menopause. Likewise, improvement of symptoms related to CD has been reported during pregnancy, but not in UC, who often experience worsening symptoms. In the colonic epithelium, estrogen receptor β (ERβ) is the predominant form of the protein expressed, and it helps maintain normal epithelial function and organization. Preclinical data suggest that ER expression and activation via estrogen confers different responses on disease severity depending on the model used to induce colitis, which may reflect what is observed in patients with IBDs. Hence, this review aims to provide an overview of estrogen and its receptors, particularly ERβ, in the pathophysiology of IBDs.
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Abstract
PURPOSE OF REVIEW Inflammatory bowel disease (IBD) affects women differently than men. This review outlines the current thinking on the impact of IBD, Crohn's disease and ulcerative colitis, on women's health. RECENT FINDINGS IBD symptoms worsen during the menstrual cycle without corelating to disease activity. Endometriosis is more frequent in women with than those without IBD. Low fertility rate is rather because of voluntary childlessness than severe disease, perianal involvement, and ileal pouch anal anastomosis (IPAA) surgery. For women with ulcerative colitis, in-vitro fertilization successfully overcomes the post-IPAA infertility. The use of biologics and thiopurines throughout pregnancy is well tolerated for both the mother and the child but the use of small molecule therapy still needs more data. These medications increase the risk of cervical cancer, anal cancer, and aggressive vulvar cancer. More screening efforts are required to keep patients healthy. Women with Crohn's disease report worse psychological well being less resilience than men but they develop more escape and avoidance strategies to cope with the disease. Depression impairs the quality of sexual life but sexual dysfunction is rarely discussed with the provider. SUMMARY Understanding the effects of sex on IBD allows personalized care and improves women's quality of life.
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Kim SE. [How Should We Do Different Approach to Treat Inflammatory Bowel Disease by Gender Difference?]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2021; 77:241-247. [PMID: 34035202 DOI: 10.4166/kjg.2021.064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 11/03/2022]
Abstract
Although not as prominent, there are gender/sex differences in incidence/prevalence, clinical manifestation and disease course, comorbidities, therapeutic response, and patients coping strategy to the disease of inflammatory bowel disease (IBD). In this review, current knowledge about gender-specific differences in IBD would be provided and how to apply this in clinical practice be discussed.
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Affiliation(s)
- Seong-Eun Kim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
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Wang Q, Li Z, Liu K, Liu J, Chai S, Chen G, Wen S, Ming T, Wang J, Ma Y, Zeng H, Liu C, Xue B. Activation of the G Protein-Coupled Estrogen Receptor Prevented the Development of Acute Colitis by Protecting the Crypt Cell. J Pharmacol Exp Ther 2021; 376:281-293. [PMID: 33318078 DOI: 10.1124/jpet.120.000216] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
G protein-coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. All of these effects were prevented by a selective GPER blocker. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 therapy inhibited the increase of cleavage caspase-3- and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. SIGNIFICANCE STATEMENT: We demonstrate that G protein-coupled estrogen receptor (GPER) activation prevents dextran sulfate sodium-induced acute colitis by protecting the crypt cells, showing that it inhibited the crypt cell apoptosis and protected proliferation of crypt cells, which resulted in protection of the intestinal mucosal barrier. This protective effect was achieved (at least in part) by inhibiting endoplasmic reticulum stress. Mucosal healing is regarded as a key therapeutic target for colitis, and GPER is expected to become a new therapeutic target for colitis.
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Affiliation(s)
- Qian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Zhao Li
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Kaixuan Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jianbo Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shiquan Chai
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Guanyu Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shuyu Wen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Tian Ming
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jiayi Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Yuntao Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Honghui Zeng
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Chuanyong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Bing Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
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Clark-Snustad K, Butnariu M, Afzali A. Women's Health and Ulcerative Colitis. Gastroenterol Clin North Am 2020; 49:769-789. [PMID: 33121695 DOI: 10.1016/j.gtc.2020.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Although ulcerative colitis affects males and females at similar rates, certain sex-specific differences influence the disease-related risks and experiences of females with ulcerative colitis. This article reviews topics that affect females with ulcerative colitis, including the impact of disease on the menstrual cycle, fertility, child bearing, sexual health, and recommendations for health care maintenance.
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Affiliation(s)
- Kindra Clark-Snustad
- Inflammatory Bowel Disease Program, Division of Gastroenterology, University of Washington, 1959 Northeast Pacific Street, Box 356424, Seattle, WA 98195, USA
| | - Madalina Butnariu
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 410 W. 10(th) Ave. 2(nd) floor, Columbus, OH 43210, USA
| | - Anita Afzali
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 395 West 12(th) Avenue, Room 280, Columbus, OH 43210, USA.
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Goodman WA, Erkkila IP, Pizarro TT. Sex matters: impact on pathogenesis, presentation and treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17:740-754. [PMID: 32901108 PMCID: PMC7750031 DOI: 10.1038/s41575-020-0354-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/27/2020] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD), as do most chronic inflammatory disorders, displays unique features and confers different risk factors in male and female patients. Importantly, sex-based differences in IBD exist for epidemiological incidence and prevalence among different age groups, with men and women developing distinct clinical symptoms and disparity in severity of disease. In addition, the presentation of comorbidities in IBD displays strong sex differences. Notably, particular issues exclusive to women's health, including pregnancy and childbirth, require specific considerations in female patients with IBD of childbearing age that can have a substantial influence on clinical outcomes. This Review summarizes the latest findings regarding sex-based differences in the epidemiology, clinical course, comorbidities and response to current therapies in patients with IBD. Importantly, the latest basic science discoveries in this area of investigation are evaluated to provide insight into potential mechanisms underlying the influence of sex on disease pathogenesis, as well as to design more personalized and efficacious care, in patients with IBD.
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Affiliation(s)
- Wendy A Goodman
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Ian P Erkkila
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Theresa T Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
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Copsel SN, Malek TR, Levy RB. Medical Treatment Can Unintentionally Alter the Regulatory T-Cell Compartment in Patients with Widespread Pathophysiologic Conditions. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2000-2012. [PMID: 32745461 DOI: 10.1016/j.ajpath.2020.07.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022]
Abstract
Regulatory T cells (Tregs) are non-redundant mediators of immune tolerance that are critical to prevent autoimmune disease and promote an anti-inflammatory tissue environment. Many individuals experience chronic diseases and physiologic changes associated with aging requiring long-term medication. Unfortunately, adverse effects accompany every pharmacologic intervention and may affect overall outcomes. We focus on medications typically prescribed during the treatment of prevalent chronic diseases and disorders, including cardiovascular disease, autoimmune disease, and menopausal symptoms, that affect >200 million individuals in the United States. Increasing studies continue to report that treatment of patients with estrogen, metformin, statins, vitamin D, and tumor necrosis factor blockers are unintentionally modulating the Treg compartment. Effects of these medications likely comprise direct and/or indirect interaction with Tregs via other immune and parenchymal populations. Differing and sometimes opposing effects on the Treg compartment have been observed using the same medication. The length of treatment, dosing regimen and stage of disease, patient age, ethnicity, and sex may account for such findings and determine the specific signaling pathways affected by the medication. Enhancing the Treg compartment can skew the patient's immune system toward an anti-inflammatory phenotype and therefore could provide unanticipated benefit. Currently, multiple medicines prescribed to large numbers of patients influence the Treg compartment; however, how such effects affect their disease outcome and long-term health remains unclear.
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Affiliation(s)
- Sabrina N Copsel
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.
| | - Thomas R Malek
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida
| | - Robert B Levy
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida
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29
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Impaired estrogen signaling underlies regulatory T cell loss-of-function in the chronically inflamed intestine. Proc Natl Acad Sci U S A 2020; 117:17166-17176. [PMID: 32632016 DOI: 10.1073/pnas.2002266117] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Signaling of 17β-estradiol (estrogen) through its two nuclear receptors, α and β (ERα, ERβ), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERβ-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERβ-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERβ-specific signaling in TGF-β-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERβ, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERβ was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERβ normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.
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30
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Meng Q, Li J, Chao Y, Bi Y, Zhang W, Zhang Y, Ji T, Fu Y, Chen Q, Zhang Q, Li Y, Bian H. β-estradiol adjusts intestinal function via ERβ and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia. Biochem Pharmacol 2020; 180:114134. [PMID: 32628929 DOI: 10.1016/j.bcp.2020.114134] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022]
Abstract
Decreases in estrogen secretion and estrogen receptor function lead to an increase in the incidence of dyslipidemia and cardiovascular disease (CVD) in postmenopausal women. We previously reported that β-estradiol has a significant regulatory effect on lipids in ApoE-/- mice with bilateral ovariectomy. In the present study, we investigated how β-estradiol regulates intestinal function via estrogen receptors to alleviate postmenopausal dyslipidemia. Ovariectomized ApoE-/- mice were treated with β-estradiol for 90 days, and we found that β-estradiol reduced TC, TG, LDL-c, IL-1β and IL-18 levels in serum and decreased lipid accumulation in the liver. β-estradiol reduced injury and inflammation in the jejunum in ovariectomized mice, and promoted the expression of tight junction-related proteins. Moreover, β-estradiol increased ERα, ERβ, GPR30 and ABCG5 protein expression, and decreased the levels of NPC1L1 and SR-B1 in the jejunum of ovariectomized mice. In Caco-2 cells incubated with cholesterol, β-estradiol up-regulated PI3K/AKT signaling, reduced cholesterol accumulation, suppressed inflammatory signaling, and increased the expression of tight junction-related proteins. ERβ or GPR30 inhibition decreased the protective effect of β-estradiol on cholesterol accumulation, tight junctions, and inflammation in cholesterol incubated Caco-2 cells, while silencing both ERβ and GPR30 completely eliminated the protective effect of β-estradiol. PI3K/AKT inhibition abolished the protective effect of β-estradiol on cholesterol accumulation, tight junction-related protein expression, and inflammation, but had no influence on ERα, ERβ or GPR30 expression in cholesterol incubated Caco-2 cells. Our results provide evidence that β-estradiol regulates intestinal function via ERβ and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia.
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Affiliation(s)
- Qinghai Meng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jun Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ying Chao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yunhui Bi
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Weiwei Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yuhan Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Tingting Ji
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yu Fu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Qi Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Qichun Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yu Li
- School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Huimin Bian
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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Rustgi SD, Kayal M, Shah SC. Sex-based differences in inflammatory bowel diseases: a review. Therap Adv Gastroenterol 2020; 13:1756284820915043. [PMID: 32523620 PMCID: PMC7236567 DOI: 10.1177/1756284820915043] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 03/03/2020] [Indexed: 02/04/2023] Open
Abstract
Sex-based differences in inflammatory bowel disease (IBD) pathogenesis, disease course, and response to therapy have been increasingly recognized, however, not fully understood. Experimental and translational models have been leveraged to investigate hypothesized mechanisms for these observed differences, including the potential modifying role of sex hormones and sex-dependent (epi)genetic and gut microbiome changes. The primary objective of this review is to comprehensively describe sex-based differences in IBD including epidemiology, pathogenesis, phenotypic differences, therapeutic response, and outcomes.
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Affiliation(s)
- Sheila D. Rustgi
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Maia Kayal
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA
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Zeng Z, Mukherjee A, Varghese AP, Yang XL, Chen S, Zhang H. Roles of G protein-coupled receptors in inflammatory bowel disease. World J Gastroenterol 2020; 26:1242-1261. [PMID: 32256014 PMCID: PMC7109274 DOI: 10.3748/wjg.v26.i12.1242] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/18/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex disease with multiple pathogenic factors. Although the pathogenesis of IBD is still unclear, a current hypothesis suggests that genetic susceptibility, environmental factors, a dysfunctional immune system, the microbiome, and the interactions of these factors substantially contribute to the occurrence and development of IBD. Although existing and emerging drugs have been proven to be effective in treating IBD, none can cure IBD permanently. G protein-coupled receptors (GPCRs) are critical signaling molecules implicated in the immune response, cell proliferation, inflammation regulation and intestinal barrier maintenance. Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases, thereby leading to the development of GPCR-targeted medication. To date, a number of GPCRs have been shown to be associated with IBD, significantly advancing the drug discovery process for IBD. The associations between GPCRs and disease activity, disease severity, and disease phenotypes have also paved new avenues for the precise management of patients with IBD. In this review, we mainly focus on the roles of the most studied proton-sensing GPCRs, cannabinoid receptors, and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Arjudeb Mukherjee
- West China School of Medicine, Sichuan University, Chengdu 410061, Sichuan Province, China
| | | | - Xiao-Li Yang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Sha Chen
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Hu Zhang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
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Jacenik D, Cygankiewicz AI, Mokrowiecka A, Małecka-Panas E, Fichna J, Krajewska WM. Sex- and Age-Related Estrogen Signaling Alteration in Inflammatory Bowel Diseases: Modulatory Role of Estrogen Receptors. Int J Mol Sci 2019; 20:ijms20133175. [PMID: 31261736 PMCID: PMC6651503 DOI: 10.3390/ijms20133175] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 06/26/2019] [Indexed: 02/07/2023] Open
Abstract
The pathogenesis of inflammatory bowel diseases (IBD) seems to be associated with alterations of immunoregulation. Several lines of evidence suggest that estrogens play a role in the modulation of immune responses and may be related to the etiology of IBD. The purpose of this work was to examine the involvement of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα), estrogen receptor β (ERβ) and ERα spliced variants ERα36 and ERα46 in Crohn's disease (CD) and ulcerative colitis (UC). The studied group included 73 patients with IBD and 31 sex and age-related controls. No differences in serum levels of 17β-estradiol nor of CYP1A1 and SULT1E1 enzymes involved in estrogen catabolism were stated. The expression pattern of estrogen receptors in tissue samples was quantified using real-time PCR and Western blotting. Statistically significant up-regulation of GPER and ERα in both CD and UC as well as down-regulation of ERβ in CD patients was found. However, differences in the expression of estrogen receptors in CD and UC have been identified, depending on the sex and age of patients. In men, up-regulation of GPER, ERα and ERα46 expression was shown in CD and UC patients. In women under 50 years of age, GPER protein level increased in UC whereas ERβ expression tended to decrease in CD and UC patients. In turn, in women over 50 the protein level of ERα increased in UC while ERβ expression decreased in CD patients. Dysregulation of estrogen receptors in the intestinal mucosa of patients with CD and UC indicates that estrogen signaling may play a role in the local immune response and maintain epithelial homeostasis in a gender- and age-dependent manner.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
| | - Adam I Cygankiewicz
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland
| | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Stefana Kopcinskiego St. 22, 90-001 Lodz, Poland
| | - Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Stefana Kopcinskiego St. 22, 90-001 Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka St. 6/8, 92-215 Lodz, Poland
| | - Wanda M Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska St. 141/143, 90-236 Lodz, Poland.
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G protein-coupled estrogen receptor mediates anti-inflammatory action in Crohn's disease. Sci Rep 2019; 9:6749. [PMID: 31043642 PMCID: PMC6494840 DOI: 10.1038/s41598-019-43233-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 01/31/2019] [Indexed: 01/05/2023] Open
Abstract
Estrogens exert immunomodulatory action in many autoimmune diseases. Accumulating evidence highlights the meaningful impact of estrogen receptors in physiology and pathophysiology of the colon. However, the significance of G protein-coupled estrogen receptor (GPER) on Crohn's disease (CD), one of the inflammatory bowel disease (IBD) types, is still elusive. Our study revealed GPER overexpression at the mRNA and protein levels in patients with CD. To evaluate the effects of GPER activation/inhibition on colitis development, a murine 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced model of CD was used. We showed that activation of GPER reduces mortality, improves macroscopic and microscopic scores and lowers C-reactive protein (CRP) level. The impact of estrogen signaling on the suppression of the intestinal inflammation was proved by immunohistochemistry. It was demonstrated that GPER activation is accompanied by modulation of extracellular-signal regulated kinase (ERK) signaling pathway and expression level of genes involved in signal transmission and immune response as well as the expression of some microRNAs (miR-145, miR-148-5p and miR-592). Our study revealed that the membrane-bound estrogen receptor GPER mediates anti-inflammatory action and seems to be a potent therapeutic target in maintaining remission in CD.
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Dietary Chitin Particles Called Mimetic Fungi Ameliorate Colitis in Toll-Like Receptor 2/CD14- and Sex-Dependent Manners. Infect Immun 2019; 87:IAI.00006-19. [PMID: 30782858 DOI: 10.1128/iai.00006-19] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 02/05/2019] [Indexed: 02/07/2023] Open
Abstract
Chitin is a natural N-acetylglucosamine polymer and a major structural component of fungal cell walls. Dietary chitin is mucoadhesive; anti-inflammatory effects of chitin microparticles (CMPs; 1- to 10-μm diameters) have been demonstrated in models of inflammatory bowel disease (IBD). The goals of this study were to assess (i) whether CMPs among various chitin preparations are the most effective against colitis in male and female mice and (ii) whether host chitin-binding Toll-like receptor 2 (TLR2) and CD14 are required for the anti-inflammatory effect of chitin. We found that colitis in male mice was ameliorated by CMPs and large chitin beads (LCBs; 40 to 70 μm) but not by chitosan (deacetylated chitin) microparticles, oligosaccharide chitin, or glucosamine. In fact, LCBs were more effective than CMPs. In female colitis, on the other hand, CMPs and LCBs were equally and highly effective. Neither sex of TLR2-deficient mice showed anti-inflammatory effects when treated with LCBs. No anti-inflammatory effect of LCBs was seen in either CD14-deficient males or females. Furthermore, an in vitro study indicated that when LCBs and CMPs were digested with stomach acidic mammalian chitinase (AMC), their size-dependent macrophage activations were modified, at least in part, suggesting reduced particle sizes of dietary chitin in the stomach. Interestingly, stomach AMC activity was greater in males than females. Our results indicated that dietary LCBs were the most effective preparation for treating colitis in both sexes; these anti-inflammatory effects of LCBs were dependent on host TLR2 and CD14.
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van der Giessen J, van der Woude CJ, Peppelenbosch MP, Fuhler GM. A Direct Effect of Sex Hormones on Epithelial Barrier Function in Inflammatory Bowel Disease Models. Cells 2019; 8:E261. [PMID: 30893871 PMCID: PMC6468635 DOI: 10.3390/cells8030261] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 03/10/2019] [Accepted: 03/14/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Pregnancy is often described as an immune-tolerant state, and a disease modulatory role for pregnancy on inflammatory bowel disease (IBD) has been suggested. The direct effect of estrogen and progesterone on the intestinal epithelial barrier is underexplored. We investigated the direct consequences of these pregnancy hormones on barrier cells and their function. METHODS We used IBD patient-derived inflammatory organoid models and 2D cell lines models. Epithelial barrier function was analyzed by measuring transepithelial electrical resistance; wound closure was determined by scratch assay; and cell viability was measured by MTT assays. Pro-inflammatory cytokine production was determined by enzyme-linked immunosorbent assays. Molecular modulation of endoplasmic reticulum (ER) stress induced by tunicamycin was studied by western blot analysis of the ER stress markers GRP78, CHOP and p-IRE1. RESULTS Progesterone and estrogen improved wound healing and epithelial barrier function in intestinal epithelial cells via upregulation of tight junction proteins. Furthermore, these sex hormones significantly reduced ER-stress and reduce pro-inflammatory cytokine production in intestinal epithelial models. CONCLUSION Our study shows that estrogen and progesterone alleviate ER stress, decrease pro-inflammatory cytokine production, stimulate wound healing, and increase barrier function of epithelial cells. Combined, these data suggest that pregnancy hormones can have beneficial effects on disease activity by positively modulating the intestinal epithelial lining.
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Affiliation(s)
- Janine van der Giessen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
| | - Gwenny M Fuhler
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015CE Rotterdam, The Netherlands.
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Veerisetty SS, Eschete SO, Uhlhorn AP, De Felice KM. Women's Health in Inflammatory Bowel Disease. Am J Med Sci 2018; 356:227-233. [PMID: 30286817 DOI: 10.1016/j.amjms.2018.05.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/23/2018] [Accepted: 05/25/2018] [Indexed: 02/07/2023]
Abstract
About half of all inflammatory bowel disease (IBD) patients are women. It is important that physicians are aware of gender-specific needs women with IBD may have. This review covers general and specific women's health issues related to their IBD. It is intended to be practical and give a brief overview of topics including body image, menstruation, contraception, cervical cancer screening, preconception counseling, anxiety, depression, pregnancy, breastfeeding, menopause, skin exams, vaccines, laboratory monitoring and bone health.
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Affiliation(s)
- Sai S Veerisetty
- Louisiana State University Health Science Center, Department of Gastroenterology, New Orleans, Louisiana
| | - Stephanie O Eschete
- Louisiana State University Health Science Center, Department of Gastroenterology, New Orleans, Louisiana
| | - Ann-Porter Uhlhorn
- Louisiana State University Health Science Center, Department of Gastroenterology, New Orleans, Louisiana
| | - Kara M De Felice
- Louisiana State University Health Science Center, Department of Gastroenterology, New Orleans, Louisiana.
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Mohammad I, Starskaia I, Nagy T, Guo J, Yatkin E, Väänänen K, Watford WT, Chen Z. Estrogen receptor α contributes to T cell–mediated autoimmune inflammation by promoting T cell activation and proliferation. Sci Signal 2018; 11:11/526/eaap9415. [DOI: 10.1126/scisignal.aap9415] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Nie X, Xie R, Tuo B. Effects of Estrogen on the Gastrointestinal Tract. Dig Dis Sci 2018; 63:583-596. [PMID: 29387989 DOI: 10.1007/s10620-018-4939-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
Estrogen is a kind of steroid compound that has extensive biologic activities. The effect of estrogen is pleiotropic, affecting multiple systems in the body. There is accumulating evidence that estrogen has important effects on the gastrointestinal tract. Longer exposure to estrogen may decrease the risk of gastric cancer. Use of the anti-estrogen drug tamoxifen might increase the risk of gastric adenocarcinoma. Estrogen receptor β may serve as a target for colorectal cancer prevention. In addition, estrogen has been reported to be closely related to the mucosal barrier, gastrointestinal function and intestinal inflammation. However, the role of estrogen in the gastrointestinal tract has not been systematically summarized. In this review, we aim to provide an overview of the role of estrogen in the gastrointestinal tract and evaluate it from various aspects, including estrogen receptors, the mucosal barrier, intestinal inflammation and gastrointestinal tract tumors, which may provide the basis for the development of therapeutic strategies to manage gastrointestinal diseases.
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Affiliation(s)
- Xubiao Nie
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China.
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Bonthala N, Kane S. Updates on Women's Health Issues in Patients with Inflammatory Bowel Disease. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2018; 16:86-100. [PMID: 29479656 DOI: 10.1007/s11938-018-0172-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
PURPOSE OF REVIEW Inflammatory bowel disease affects approximately 800,000 women in the USA with the peak incidence between ages 15 to 40. Thus for many females, IBD can impact nearly every stage of their life from menarche to pregnancy, menopause, and beyond. This paper will review the most recent updates on the topics of sexual health, cervical cancer screening, menstruation, fertility, contraception, and menopause. RECENT FINDINGS Menarche can be delayed in females especially those who are underweight, malnourished, or with active inflammatory bowel disease. Cyclical GI symptoms during a menstrual cycle are very common in women with IBD and should not be confused with flares. Overall fertility is similar to the general population unless females with IBD have had significant abdominal surgery but reassuringly this infertility appears to be restored with the use of in vitro fertilization. Discussion regarding family planning is imperative in women with IBD with a strong recommendation to consider long-acting highly effective contraceptives such as intrauterine devices or implants. Cervical cancer screening should be tailored in women on immunosuppressive medications and all women under 26 years of age should be advised to receive the human papilloma virus vaccination. As gastroenterologists will have longitudinal relationships with their female IBD patients, they must be knowledgeable about sex-specific issues during each stage of life from puberty to after menopause to optimize their patient's care.
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Affiliation(s)
- Nirupama Bonthala
- Inflammatory Bowel Disease Center, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Sunanda Kane
- Department of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
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Rolston VS, Boroujerdi L, Long MD, McGovern DPB, Chen W, Martin CF, Sandler RS, Carmichael JD, Dubinsky M, Melmed GY. The Influence of Hormonal Fluctuation on Inflammatory Bowel Disease Symptom Severity-A Cross-Sectional Cohort Study. Inflamm Bowel Dis 2018; 24:387-393. [PMID: 29361085 PMCID: PMC6196767 DOI: 10.1093/ibd/izx004] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Indexed: 01/12/2023]
Abstract
BACKGROUND Many women with inflammatory bowel disease (IBD) report changes in symptoms in association with hormonal changes during menses, pregnancy, and hormonal contraceptive use, suggesting a hormonal influence on disease activity. We aimed to identify and characterize IBD symptom fluctuations in women during times of hormonal variation. METHODS From June 2012 through September 2012, women enrolled in Crohn's and Colitis Foundation of America Partners , an online Internet cohort of patients with IBD, were invited to participate in this study. Using a 5-point Likert scale, participants were asked to rate symptom changes during their menstrual cycle, pregnancy, the postpartum period, and after menopause. Clinical and demographic differences were assessed using univariate and multivariable methods. RESULTS A total of 1,203 female patients with Crohn's disease (CD) and ulcerative colitis (UC) participated (64% CD, 34% UC). Over half of the women with IBD reported worsening symptoms during menses. Symptom changes were similar between women with CD vs UC, except in pregnancy, where symptom worsening during pregnancy was more commonly seen in UC than CD (P = 0.02). Overall, women reporting symptom worsening were younger at the time of IBD diagnosis (P < 0.01), had lower quality of life (SIBDQ) scores (P < 0.01), and had a higher BMI (25 vs 24) than women without symptom worsening. CONCLUSIONS Women with IBD report changes in symptom severity during times of hormone fluctuation. Further clarification of the role of hormones in IBD is warranted in order to understand these relationships and to identify potential management strategies for women with IBD and hormonally sensitive gastrointestinal symptoms.
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Affiliation(s)
- Vineet S Rolston
- F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles
| | | | - Millie D Long
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill
| | - Dermot P B McGovern
- F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles
| | - Wenli Chen
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill
| | - Christopher F Martin
- Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai New York
| | - Robert S Sandler
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill
| | - John D Carmichael
- F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles
| | - Marla Dubinsky
- Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai New York
| | - Gil Y Melmed
- F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles,Address correspondence to: Gil Y. Melmed, MD, MS, 8730 Alden Dr, Thalians Bldg 239E, Los Angeles, CA 90048. E-mail:
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Significance of intratissue estrogen concentration coupled with estrogen receptors levels in colorectal cancer prognosis. Oncotarget 2017; 8:115546-115560. [PMID: 29383180 PMCID: PMC5777792 DOI: 10.18632/oncotarget.23309] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 12/05/2017] [Indexed: 12/17/2022] Open
Abstract
Dysregulation of estrogen related pathways is implicated colorectal cancer (CRC) development. However, significance of intratissue concentration of estrone (E1) and 17β-estradiol (E2) in relation to estrogen receptor (ESR) expression level was not addressed so far. Herein, we measured E1 and E2 intratissue concentration using liquid chromatography electrospray ionization tandem mass spectrometry (ESI LC/MS) and mRNA levels of ESR1 and ESR2 using RT-qPCR in cancerous and histopathologically unchanged tissue from 75 and 110 CRC patients, respectively. The obtained results were associated with clinicopathological factors, expression of estrogen dependent genes (CTNNB1, CCND1) and prognostic significance. We found no statistically significant differences in E1 or E2 concentration between cancerous tissue and histopathologically unchanged counterparts. Moreover, mRNA levels of ESR1 and ESR2 were significantly decreased in cancerous tissue compared with histopathologically unchanged (p=0.00001). Log rank analysis revealed no benefit of low E1 to E2 ratio, high E1, E2 concentration or ESR1, ESR2 mRNA level for patients’ overall (OS) and disease free survival (DFS). Interestingly, we have observed that patients with low ESR1 mRNA level coupled with low E1 intratissue concentration had a significant decrease in DFS compared with group of patients with high ESR1 mRNA level and high E1 concentration (HR=0.16, 95% CI 0.02-1.05; p=0.06). Furthermore, patients with low E1 concentration and low ESR1 transcript had significantly higher CTNNB1 and CCND1 mRNA level compare with subgroup with high level of both grouping factors. Our study indicates a potential value of estrogen intratissue concentration and its receptor expression level for CRC patients’ prognosis.
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Linares PM, Algaba A, Urzainqui A, Guijarro-Rojas M, González-Tajuelo R, Garrido J, Chaparro M, Gisbert JP, Bermejo F, Guerra I, Castellano V, Fernández-Contreras ME. Ratio of Circulating Estrogen Receptors Beta and Alpha (ERβ/ERα) Indicates Endoscopic Activity in Patients with Crohn's Disease. Dig Dis Sci 2017; 62:2744-2754. [PMID: 28823012 DOI: 10.1007/s10620-017-4717-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 08/07/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND Data supporting a role of female hormones and/or their receptors in inflammatory bowel disease (IBD) are increasing, but most of them are derived from animal models. Estrogen receptors alpha (ERα) and beta (ERβ) participate in immune and inflammatory response, among a variety of biological processes. Their effects are antagonistic, and the net action of estrogens may depend on their relative proportions. AIM To determine the possible association between the balance of circulating ERβ and ERα (ERβ/ERα) and IBD risk and activity. METHODS Serum samples from 145 patients with IBD (79 Crohn's disease [CD] and 66 ulcerative colitis [UC]) and 39 controls were retrospectively studied. Circulating ERα and ERβ were measured by ELISA. Disease activities were assessed by clinical and endoscopic indices specific for CD and UC. RESULTS Low values of ERβ/ERα ratio were directly associated with clinical (p = 0.019) and endoscopic (p = 0.002) disease activity. Further analyses by type of IBD confirmed a strong association between low ERβ/ERα ratio and CD clinical (p = 0.011) and endoscopic activity (p = 0.002). The receiver operating curve (ROC) analysis showed that an ERβ/ERα ratio under 0.85 was a good marker of CD endoscopic activity (area under the curve [AUC]: 0.84; p = 0.002; sensitivity: 70%; specificity: 91%). ERβ/ERα ratio was not useful to predict UC activity. CONCLUSIONS An ERβ/ERα ratio under 0.85 indicated CD endoscopic activity. The determination of serum ERβ/ERα might be a useful noninvasive screening tool for CD endoscopic activity.
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Affiliation(s)
- Pablo M Linares
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain
| | - Alicia Algaba
- Department of Gastroenterology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - Ana Urzainqui
- Department of Immunology, Hospital Universitario de la Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain
| | - Mercedes Guijarro-Rojas
- Department of Pathology, Hospital Universitario de la Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain
| | - Rafael González-Tajuelo
- Department of Immunology, Hospital Universitario de la Princesa, IIS-IP, C/ Diego de León 62, 28006, Madrid, Spain
| | - Jesús Garrido
- Department of Social Psychology and Methodology, School of Psychology, Universidad Autónoma de Madrid (UAM), C/ Ivan Pavlov 6. Ciudad Universitaria de Cantoblanco, 28049, Madrid, Spain
| | - María Chaparro
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain
| | - Javier P Gisbert
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain
| | - Fernando Bermejo
- Department of Gastroenterology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - Iván Guerra
- Department of Gastroenterology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - Víctor Castellano
- Department of Pathology, Hospital Universitario de Fuenlabrada, C/ Camino del Molino 2, 28942, Fuenlabrada-Madrid, Spain
| | - María-Encarnación Fernández-Contreras
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), C/ Diego de León 62, 28006, Madrid, Spain. .,Departments of Anatomy I and Immunology, School of Medicine, Universidad Alfonso X El Sabio (UAX), Avda. de la Universidad 1, 28691, Villanueva de la Cañada, Madrid, Spain.
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Donaldson EK, Huang V, Ross S, Sydora BC. Experience of menopause in women with inflammatory bowel disease: pilot study. Climacteric 2017; 20:545-551. [DOI: 10.1080/13697137.2017.1360861] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- E. Kaley Donaldson
- Department of Obstetrics & Gynecology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - V. Huang
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - S. Ross
- Department of Obstetrics & Gynecology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
| | - B. C. Sydora
- Department of Obstetrics & Gynecology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
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Yang X, Guo Y, He J, Zhang F, Sun X, Yang S, Dong H. Estrogen and estrogen receptors in the modulation of gastrointestinal epithelial secretion. Oncotarget 2017; 8:97683-97692. [PMID: 29228643 PMCID: PMC5722595 DOI: 10.18632/oncotarget.18313] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 05/22/2017] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal (GI) epithelial ion transport is physiologically important in many aspects of humans, such as in maintaining fluid balance of whole body, and also plays a role in the development and progression of common GI disease. Estrogen and estrogen receptors have been shown to modulate the activity of epithelial ion secretion in GI tract. This review aims to address the current state of knowledge about the role of estrogen and estrogen receptors in modulation of GI epithelial secretion and to elucidate the underlying mechanisms. We highlight the recent findings regarding the importance of estrogen and estrogen receptors in GI epithelia protection and body fluid balance by modulation of gastrointestinal epithelial HCO3- and Cl- secretion, especially current information about the regulatory mechanisms of duodenal HCO3- secretion based on our study in this field. Since there are no reviews on this topic but only few papers to address the main issues, we hope to timely provide new perspectives for the association between estrogen and GI disease.
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Affiliation(s)
- Xin Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Yanjun Guo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Jialin He
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Fenglian Zhang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Xuemei Sun
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Shiming Yang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Hui Dong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China.,Division of Gastroenterology, Department of Medicine, School of Medicine, University of California, San Diego, California, USA
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Pierdominici M, Maselli A, Varano B, Barbati C, Cesaro P, Spada C, Zullo A, Lorenzetti R, Rosati M, Rainaldi G, Limiti MR, Guidi L, Conti L, Gessani S. Linking estrogen receptor β expression with inflammatory bowel disease activity. Oncotarget 2016; 6:40443-51. [PMID: 26497217 PMCID: PMC4747344 DOI: 10.18632/oncotarget.6217] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 10/02/2015] [Indexed: 12/13/2022] Open
Abstract
Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)β expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = 27) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-α therapy and responsive to treatment, ERβ expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERβ expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERβ expression inversely correlated with interleukin (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERβ downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of endoscopic disease activity.
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Affiliation(s)
- Marina Pierdominici
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Angela Maselli
- Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Barbara Varano
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Cristiana Barbati
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Paola Cesaro
- Digestive Endoscopy Unit, Catholic University, Rome, Italy
| | | | - Angelo Zullo
- Gastroenterology and Digestive Endoscopy, Nuovo Regina Margherita Hospital, Rome, Italy
| | - Roberto Lorenzetti
- Gastroenterology and Digestive Endoscopy, Nuovo Regina Margherita Hospital, Rome, Italy
| | - Marco Rosati
- Histopathology Complex Unit, Santo Spirito Hospital, Rome, Italy
| | - Gabriella Rainaldi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | | | - Luisa Guidi
- IBD Unit, Complesso Integrato Columbus, Catholic University, Rome, Italy
| | - Lucia Conti
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Sandra Gessani
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
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Abegunde AT, Muhammad BH, Ali T. Preventive health measures in inflammatory bowel disease. World J Gastroenterol 2016; 22:7625-7644. [PMID: 27678347 PMCID: PMC5016364 DOI: 10.3748/wjg.v22.i34.7625] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 08/10/2016] [Accepted: 08/30/2016] [Indexed: 02/06/2023] Open
Abstract
We aim to review the literature and provide guidance on preventive health measures in inflammatory bowel disease (IBD). Structured searches were performed in PubMed, MEDLINE, EMBASE, Web of Science and Cochrane Library from January 1976 to June 2016 using the following keywords: (inflammatory bowel disease OR Crohn’s disease OR ulcerative colitis) AND (health maintenance OR preventive health OR health promotion). Abstracts of the articles selected from each of these multiple searches were reviewed, and those meeting the inclusion criteria (that is, providing data regarding preventive health or health maintenance in IBD patients) were recorded. Reference lists from the selected articles were manually reviewed to identify further relevant studies. Patients with IBD are at increased risk of developing adverse events related to the disease course, therapeutic interventions, or non-adherence to medication. Recent studies have suggested that IBD patients do not receive preventive services with the same thoroughness as patients with other chronic diseases. Preventive health measures can avert morbidity and improve the quality of life of patients with IBD. Gastroenterologists and primary care physicians (PCPs) should have an up to date working knowledge of preventive health measures for IBD patients. A holistic approach and better communication between gastroenterologists and PCPs with explicit clarification of roles will prevent duplication of services and streamline care.
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Abegunde AT, Muhammad BH, Bhatti O, Ali T. Environmental risk factors for inflammatory bowel diseases: Evidence based literature review. World J Gastroenterol 2016; 22:6296-6317. [PMID: 27468219 PMCID: PMC4945988 DOI: 10.3748/wjg.v22.i27.6296] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/19/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: Advances in genetics and immunology have contributed to the current understanding of the pathogenesis of inflammatory bowel diseases (IBD).
METHODS: The current opinion on the pathogenesis of IBD suggests that genetically susceptible individuals develop intolerance to dysregulated gut microflora (dysbiosis) and chronic inflammation develops as a result of environmental insults. Environmental exposures are innumerable with varying effects during the life course of individuals with IBD. Studying the relationship between environmental factors and IBD may provide the missing link to increasing our understanding of the etiology and increased incidence of IBD in recent years with implications for prevention, diagnosis, and treatment. Environmental factors are heterogeneous and genetic predisposition, immune dysregulation, or dysbiosis do not lead to the development of IBD in isolation.
RESULTS: Current challenges in the study of environmental factors and IBD are how to effectively translate promising results from experimental studies to humans in order to develop models that incorporate the complex interactions between the environment, genetics, immunology, and gut microbiota, and limited high quality interventional studies assessing the effect of modifying environmental factors on the natural history and patient outcomes in IBD.
CONCLUSION: This article critically reviews the current evidence on environmental risk factors for IBD and proposes directions for future research.
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Klil-Drori AJ, Tascilar K, Yin H, Aprikian A, Bitton A, Azoulay L. Androgen Deprivation Therapy and the Incidence of Inflammatory Bowel Disease in Patients With Prostate Cancer. Am J Epidemiol 2016; 184:15-22. [PMID: 27268031 PMCID: PMC4929242 DOI: 10.1093/aje/kwv307] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 11/03/2015] [Indexed: 12/12/2022] Open
Abstract
Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. By lowering androgen levels, ADT inhibits the progression of prostate cancer, but it may also affect gut autoimmunity. We investigated the association between ADT and the incidence of inflammatory bowel disease using a cohort of 31,842 men newly diagnosed with prostate cancer between 1988 and 2014, identified in the United Kingdom Clinical Practice Research Datalink. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays, with nonuse as the reference category. During 133,018 person-years of follow-up, 48 men were newly diagnosed with ulcerative colitis (incidence rate (IR) = 36/100,000 person-years (PY)) and 12 were diagnosed with Crohn's disease (IR = 9/100,000 PY). In Cox proportional hazards models, ADT was associated with a decreased risk of ulcerative colitis (IR = 24/100,000 PY vs. IR = 50/100,000 PY; hazard ratio = 0.52, 95% confidence interval: 0.28, 0.99) and a nonsignificant decreased risk of Crohn's disease (hazard ratio = 0.38, 95% confidence interval: 0.11, 1.37). These findings indicate that the use of ADT may be associated with intestinal autoimmunity. Further research is warranted to replicate these findings and assess their clinical significance.
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Affiliation(s)
| | | | | | | | | | - Laurent Azoulay
- Correspondence to Dr. Laurent Azoulay, Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine, H-425.1, Montreal, QC H3T 1E2, Canada (e-mail: )
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Bábíčková J, Tóthová Ľ, Lengyelová E, Bartoňová A, Hodosy J, Gardlík R, Celec P. Sex Differences in Experimentally Induced Colitis in Mice: a Role for Estrogens. Inflammation 2016; 38:1996-2006. [PMID: 25962374 DOI: 10.1007/s10753-015-0180-7] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sex differences have been found in the incidence and progression of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. The reported differences in observational studies are controversial, and the effects of sex hormones on the pathogenesis of IBD are not clear. The aim of this study was to analyze sex differences in the progression of experimentally induced colitis. Experimental colitis was induced in adult mice by adding 2% dextran sodium sulfate (DSS) into drinking water. Male and female mice were used as intact, gonadectomized, and supplemented with either estradiol or testosterone. In comparison to males, female mice with induced colitis had significantly longer colon (p < 0.05), lower decrease in body weight (p < 0.001), and lower stool consistency score (p < 0.05). Histopathological analysis showed less inflammatory infiltrates (p < 0.001) and crypt damage (p < 0.001) in female mice. Female mice with colitis had also lower concentration of TNF-α in colon homogenates (p < 0.01). Supplementation with estradiol in ovariectomized mice ameliorated the severity of colitis. Female mice are partially protected against chemically induced colitis. This protection seems to be mediated by estradiol.
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Affiliation(s)
- Janka Bábíčková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08, Bratislava, Slovakia,
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