Gynaecological Disorders in Not-celiac Wheat Sensitivity

NCT03027492 | Completed

• 1 other identifier: ACPM15
• Study Type: interventional
• Target: 500
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Non-celiac Wheat Sensitivity

Keywords

Non-celiac Wheat Sensitivity; gynaecological disorders; gluten-free diet; celiac disease; irritable bowel syndrome

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Gynaecological disorders in NCWS female patients after gluten-free diet.

  Change from baseline to at leats 6 months of gluten-free diet

• PAP test in NCWS female patients after gluten-free diet.

  Change from baseline at 6 months of gluten-free diet

• PAP test in NCWS female patients after 7-day open challenge with wheat.

  After at least 6 months of gluten-free diet

Study Arms (8)

1. NCWS retrospective patients

ACTIVE COMPARATOR

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

2. CD retrospective control patients

ACTIVE COMPARATOR

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

3. IBS retrospective control patients

ACTIVE COMPARATOR

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

4. NCWS prospective patients

ACTIVE COMPARATOR

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

5. CD prospective control patients

ACTIVE COMPARATOR

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

6. IBS prospective control patients

ACTIVE COMPARATOR

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

7. Healthy female controls

NO INTERVENTION

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.

8. NCWS femal patients open challenge with wheat

ACTIVE COMPARATOR

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

Interventions

Gluten free diet OTHER

The investigators will evaluate the modification of gynaecological disorder after a gluten (wheat)-free diet.

1. NCWS retrospective patients; 2. CD retrospective control patients; 3. IBS retrospective control patients; 4. NCWS prospective patients; 5. CD prospective control patients; 6. IBS prospective control patients

NCWS open challenge with wheat OTHER

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).

8. NCWS femal patients open challenge with wheat

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• To diagnose NCWS the recently proposed criteria will be adopted. All the patients will meet the following criteria:
• age ≥18 years and ≤65 years;
• 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;
• 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;
• 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.

You may not qualify if:

• self-elimination of wheat from the diet and refusal to reintroduce it for a diagnostic purpose, before entering in to the study;
• treatment with corticosteroids and non steroidal anti-inflammatory (FANS) drugs during the 2 weeks before the duodenal biopsies;
• EMA positivity in the culture medium of duodenal biopsies (EMA biopsy), even with a normal villo/crypt ratio in the mucosa;
• pregnancy or breastfeeding;
• alcohol and/or drug abuse;
• 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.

Sponsors & Collaborators

• University of Palermo: lead

Study Sites (3)

Department of Internal Medicine, Giovanni Paolo II Hospital

Sciacca, Agrigento, 92019, Italy

Location

Department of Internal Medicine, University Hospital

Palermo, Palermo, 90129, Italy

Location

Internal Medicine Unit, 'V. Cervello' Hospital

Palermo, Palermo, 90146, Italy

Location

Related Publications (7)

• 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.

  PMID: 27388423 RESULT

• 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.

  PMID: 26109796 RESULT

• 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.

  PMID: 25430806 RESULT

• 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.

  PMID: 24533607 RESULT

• 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.

  PMID: 24275240 RESULT

• 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.

  PMID: 24169272 RESULT

• 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.

  PMID: 22825366 RESULT

MeSH Terms

Conditions

Celiac Disease; Irritable Bowel Syndrome

Interventions

Diet, Gluten-Free; Flour

Condition Hierarchy (Ancestors)

Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Colonic Diseases, Functional; Colonic Diseases

Intervention Hierarchy (Ancestors)

Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena; Food; Food and Beverages

Study Officials

• Antonio Carroccio, MD

  University of Palermo

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: December 30, 2016
• First Posted: January 23, 2017
• Study Start: January 1, 2001
• Primary Completion: July 1, 2021
• Study Completion: July 31, 2025
• Last Updated: April 14, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (3)