Gynaecological Disorders in Not-celiac Wheat Sensitivity

Gynaecological Disorders in Patients With Not-celiac Wheat Sensitivity

In the last few years, a new clinical entity has emerged which includes patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy. This clinical condition has been named non-celiac gluten sensitivity (NCGS), although in a recent article, the investigators suggested the term "non-celiac wheat sensitivity" (NCWS), because it is not known to date what component of wheat actually causes the symptoms. The clinical picture of NCWS is characterized by combined gastrointestinal (bloating, abdominal pain, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and very different extra-intestinal and systemic manifestations (headache, depression, anxiety, 'foggy mind,' tiredness, dermatitis or skin rash, fibromyalgia-like joint/muscle pain, leg or arm numbness, and anemia). Nowadays, there no data about a possible relationship between gynaecological disorders and food ingestion and food allergy/intolerance. Therefore, the aims of the present study are to investigate 1) the prevalence and characteristics of gynaecological disorders in NCWS patients compared to healthy, CD and irritable bowel syndrome (IBS) controls, 2) the modification of such disorders in NCWS patients after a gluten (wheat)-free diet, and 3) whether cytological alterations could be identified on samples taken during Papanicolaou (PAP) tests performed in NCWS patients with uro-gynecological disorders on strict WFD and after a 7-day open challenge with wheat.

Study Overview

• Status: Completed
• Conditions: Non-celiac Wheat Sensitivity
• Intervention / Treatment: Other: Gluten free diet; Other: NCWS open challenge with wheat

Detailed Description

In the last few years, a new clinical entity has emerged which includes patients who consider themselves to be suffering from problems caused by wheat and/or gluten ingestion, even though they do not have CD or wheat allergy. This clinical condition has been named non-celiac gluten sensitivity (NCGS), although in a recent article, the investigators suggested the term "non-celiac wheat sensitivity" (NCWS), because it is not known to date what component of wheat actually causes the symptoms. Other areas of doubt in NCWS regard its pathogenesis, while some papers reported intestinal immunologic activation, others linked NCWS to the dietary short chain carbohydrate (fermentable oligo-di-monosaccharides and polyols, FODMAPs) load. The investigators recently demonstrated that higher proportions of patients with NCWS develop autoimmune disorders, are antinuclear antibodies (ANA) positive, and show DQ2/DQ8 haplotypes compared with patients with IBS, supporting an immunologic involvement in NCWS. The clinical picture of NCWS is characterized by combined gastrointestinal (bloating, abdominal pain, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and very different extra-intestinal and systemic manifestations (headache, depression, anxiety, 'foggy mind,' tiredness, dermatitis or skin rash, fibromyalgia-like joint/muscle pain, leg or arm numbness, and anemia). Nowadays, there no data about a possible relationship between gynaecological disorders (i.e. menstrual cycle alterations, vaginitis, recurrent vulvovaginitis, recurrent cystitis, chronic pelvic pain, recurrent pregnancy loss, infertility) and food ingestion and food allergy/intolerance. Therefore, the aims of the present study are to investigate 1) the prevalence and characteristics of gynaecological disorders in NCWS patients compared to healthy, CD and IBS controls, 2) the modification of such disorders in NCWS patients after a gluten (wheat)-free diet, and 3) whether cytological alterations could be identified on samples taken during Papanicolaou (PAP) tests performed in NCWS patients with uro-gynecological disorders on strict WFD and after a 7-day open challenge with wheat.

• Study Type: Interventional
• Enrollment (Actual): 500
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Agrigento
    • Sciacca, Agrigento, Italy, 92019
      • Department of Internal Medicine, Giovanni Paolo II Hospital
  • Palermo
    • Palermo, Palermo, Italy, 90129
      • Department of Internal Medicine, University Hospital
    • Palermo, Palermo, Italy, 90146
      • Internal Medicine Unit, 'V. Cervello' Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

To diagnose NCWS the recently proposed criteria will be adopted. All the patients will meet the following criteria:

1. age ≥18 years and ≤65 years;
2. negative serum assays for celiac disease: anti-deamidated gliadin peptide (anti-DGP) Ig (Immunoglobulin)A and IgG antibodies, anti-tissue transglutaminase (anti-tTG) IgA and IgG antibodies, and anti-endomysium (anti-EMA) IgA antibodies;
3. absence of duodenal villous atrophy, documented in all the patients carrying the DQ2 and/or DQ8 Human Leukocyte Antigens (HLA) haplotypes, evaluated during the ingestion of at least 100g of bread and/or pasta every day for at least 45 days;
4. exclusion of IgE-mediated wheat allergy, documented by a negative skin prick-test and/or serum dosage of IgE specific for wheat, gluten and gliadin;
5. complete resolution of symptoms after a strict standard elimination diet (oligoantigenic diet, free of wheat, cow's milk, eggs, tomatoes, chocolate, and other foods self-reported by patient as cause of symptoms) continued for at least 4 weeks, followed by the recurrence of symptoms after double-blind placebo-controlled wheat challenge or open challenges for the others self-reported foods;

To diagnose CD the standard criteria will be adopted. All the patients will meet the following criteria:

• positive serum anti-transglutaminase (anti-tTG) and anti-endomysium (EmA) immunoglobulin (Ig)A and IgG antibodies
• presence of intestinal villous atrophy;

To diagnose IBS the standard Rome II (for retrospective patients) and Rome III (for prospective patients) Criteria will be adopted. None of these subjects improved on an elimination diet without wheat, cow's milk, egg, tomato, or chocolate.

Exclusion Criteria:

For NCWS diagnosis it will be evaluated the following exclusion criteria:

1. self-elimination of wheat from the diet and refusal to reintroduce it for a diagnostic purpose, before entering in to the study;
2. treatment with corticosteroids and non steroidal anti-inflammatory (FANS) drugs during the 2 weeks before the duodenal biopsies;
3. EMA positivity in the culture medium of duodenal biopsies (EMA biopsy), even with a normal villo/crypt ratio in the mucosa;
4. pregnancy or breastfeeding;
5. alcohol and/or drug abuse;
6. chronic inflammatory bowel disease or other intestinal organic disease; nervous system disease or major psychiatric disorders; infectious diseases; immunological deficits and physical impairments; 7) diagnosis of uro-gynecological organic diseases (uro-genital infections, endometriosis, neoplasms, etc.), confirmed by an uro-gynecologist both before the diagnosis of NCWS and during the follow-up period.

Additional specific inclusion/exclusion criteria for NCWS patients were used in this study: 1) female patient complaining of uro-gynecological disorders; 2) at least one uro-gynecological visit, including an uro-gynecological ultrasound and microbiological tests, that excluded uro-gynecological organic diseases within 6 months before the recruitment in the study; 3) follow-up period of at least 12 months after the initial diagnosis of NCWS and at least 2 outpatient, every 6 months, visits during the follow-up; 4) strict adherence to WFD 12 months after NCWS diagnosis.

Healthy controls had to respect the following inclusion criteria: 1) female gender; 2) age ≥18 years and ≤65 years; 3) negative serology for anti- Deamidated Gliadin Peptide (DGP) IgA and IgG antibodies, anti-tissue TransGlutaminase (tTG) IgA and IgG antibodies; 4) absence of self-reported symptoms related to wheat intake; 5) at least one uro-gynecological visit, including an uro-gynecological ultrasound and microbiological tests, that excluded uro-gynecological organic diseases within 6 months before the recruitment in the study.

Additional exclusion criteria for both NCWS patients and healthy controls were: 1) use of drugs potentially causes of the uro-gynecological disorders; 2) diagnosis of uro-gynecological organic diseases (uro-genital infections, endometriosis, neoplasms, etc.), confirmed by an uro-gynecologist; 3) previous surgical interventions on the uro-genital system; 4) absence of signed informed consent form.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1. NCWS retrospective patients; The clinical charts of NCWS female patients attending the outpatient centers of the Department of Internal Medicine at the University Hospital of Palermo, Italy, the Department of Internal Medicine of the Hospital of Sciacca, Agrigento, Italy, and the Internal Medicine Unit, 'V. Cervello' Hospital of Palermo, Italy, will be reviewed with a retrospective method. They had all been diagnosed with NCWS between January 2001 and June 2024 and included in a previously published study. These charts included specific sections for associated gynaecological disorders. Incomplete clinical charts will be excluded. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.	Other: Gluten free diet; The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.
Active Comparator: 2. CD retrospective control patients; To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of CD female patients had been randomly chosen by a computer-generated method from female patients diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group was asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.	Other: Gluten free diet; The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.
Active Comparator: 3. IBS retrospective control patients; To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of IBS female patients had been randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group was asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.	Other: Gluten free diet; The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.
Active Comparator: 4. NCWS prospective patients; The investigators prospectively will survey adult female patients with functional gastroenterological symptoms according to the Rome III criteria, and a suspected diagnosis of NCWS. The patients will be recruited between January 2017 and December 2024 at the same 3 centers. Most of the patients will be referred owing to gastrointestinal and extraintestinal symptoms, the onset of which, they reported, could be related to wheat ingestion. In addition, patients will be asked about the presence and characteristics of gynaecological disorders using an ad hoc questionnaire. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.	Other: Gluten free diet; The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.
Active Comparator: 5. CD prospective control patients; To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of CD female patients will be randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group will be asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.	Other: Gluten free diet; The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.
Active Comparator: 6. IBS prospective control patients; To compare the presence and characteristics of gynaecological disorders in NCWS female patients, a control group of IBS female patients will be randomly chosen by a computer-generated method from female subjects diagnosed during the same period (2001-2024) and in the same centers, and age- (+2 years) matched with the NCWS female patients. Similar to NCWS patients, also this control group will be asked for gynaecological disorders and the answers reported in the patients clinical charts. All the patients will be evaluated at baseline (i.e. at diagnosis) and after at least a 6-months period of gluten-free diet.	Other: Gluten free diet; The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.
No Intervention: 7. Healthy female controls; During the same period (2011-2024), age-matched healthy female controls have been consecutively recruited in several General Practitioners (GPs) outpatients' clinics of Palermo, Italy.
Active Comparator: 8. NCWS femal patients open challenge with wheat; In a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina).	Other: NCWS open challenge with wheat; In a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gynaecological disorders in NCWS female patients at baseline	Prevalence of gynaecological disorders in retrospective and prospective NCWS female patients, compared to retrospective and prospective CD and IBS female patients.	Up to 200 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gynaecological disorders in NCWS female patients after gluten-free diet.	Gynaecological disorders evaluation after at least 6 months of gluten-free diet after the NCWS diagnosis, by visual analogic scales, specific questionnaire, and clinical examination, both in retrospective and prospective NCWS female patients.	Change from baseline to at leats 6 months of gluten-free diet
PAP test in NCWS female patients after gluten-free diet.	PAP smear after at least 6 months of gluten-free diet after the NCWS diagnosis, both in retrospective and prospective NCWS female patients.	Change from baseline at 6 months of gluten-free diet
PAP test in NCWS female patients after 7-day open challenge with wheat.	In a small group of NCWS patients a cervical-vaginal PAP test was performed during 'strict' WFD and then repeated after a single 7-day open challenge with wheat (patients were invited to continue their strict WFD adding 80g/die of Triticum aestivum flour which should be cooked and eaten as semolina).	After at least 6 months of gluten-free diet

Collaborators and Investigators

• Sponsor: University of Palermo
• Investigators: Study Director: Antonio Carroccio, MD, University of Palermo

Publications and helpful links

General Publications

• Mansueto P, Seidita A, D'Alcamo A, Carroccio A. Non-celiac gluten sensitivity: literature review. J Am Coll Nutr. 2014;33(1):39-54. doi: 10.1080/07315724.2014.869996.
• Carroccio A, Mansueto P, Iacono G, Soresi M, D'Alcamo A, Cavataio F, Brusca I, Florena AM, Ambrosiano G, Seidita A, Pirrone G, Rini GB. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol. 2012 Dec;107(12):1898-906; quiz 1907. doi: 10.1038/ajg.2012.236. Epub 2012 Jul 24.
• Carroccio A, Soresi M, D'Alcamo A, Sciume C, Iacono G, Geraci G, Brusca I, Seidita A, Adragna F, Carta M, Mansueto P. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: a prospective observation study. BMC Med. 2014 Nov 28;12:230. doi: 10.1186/s12916-014-0230-2.
• Carroccio A, Rini G, Mansueto P. Non-celiac wheat sensitivity is a more appropriate label than non-celiac gluten sensitivity. Gastroenterology. 2014 Jan;146(1):320-1. doi: 10.1053/j.gastro.2013.08.061. Epub 2013 Nov 22. No abstract available.
• Carroccio A, Mansueto P, D'Alcamo A, Iacono G. Non-celiac wheat sensitivity as an allergic condition: personal experience and narrative review. Am J Gastroenterol. 2013 Dec;108(12):1845-52; quiz 1853. doi: 10.1038/ajg.2013.353. Epub 2013 Nov 5.
• Di Liberto D, Mansueto P, D'Alcamo A, Lo Pizzo M, Lo Presti E, Geraci G, Fayer F, Guggino G, Iacono G, Dieli F, Carroccio A. Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet. Clin Transl Gastroenterol. 2016 Jul 7;7(7):e178. doi: 10.1038/ctg.2016.35.
• Mansueto P, D'Alcamo A, Seidita A, Carroccio A. Food allergy in irritable bowel syndrome: The case of non-celiac wheat sensitivity. World J Gastroenterol. 2015 Jun 21;21(23):7089-109. doi: 10.3748/wjg.v21.i23.7089.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2001
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 31, 2025

Study Registration Dates

• First Submitted: December 30, 2016
• First Submitted That Met QC Criteria: January 17, 2017
• First Posted (Estimated): January 23, 2017

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: gluten-free diet; celiac disease; irritable bowel syndrome; Non-celiac Wheat Sensitivity; gynaecological disorders
• Additional Relevant MeSH Terms: Metabolic Diseases; Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Malabsorption Syndromes; Colonic Diseases, Functional; Nutritional and Metabolic Diseases; Irritable Bowel Syndrome; Celiac Disease; Therapeutics; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Nutritional Physiological Phenomena; Diet Therapy; Nutrition Therapy; Diet; Diet, Gluten-Free; Flour
• Other Study ID Numbers: ACPM15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No