The Role of Dysbiosis of Gut Microbiota in the Pathogenesis of PCOS.

NCT ID: NCT03843736

Last Updated: 2019-10-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-21
• Study Completion Date: 2020-12-31

Brief Summary

Polycystic ovary syndrome (PCOS) has a significant impact on women's health, but its pathogenesis is not yet clear. Dysbiosis of gut microbiota may play a role in the pathological change of PCOS. Most of the current researches are still limited to the use of amplicon sequencing to compare the basic taxonomic differences of gut microbiota between PCOS patients and normal controls. Overall analysis of microbiome species, genes, function, metabolism, and immunity in PCOS is still lacked. In this research, we would perform metagenomic sequencing to find the characteristics of gut microbiota of PCOS and to explore their correlations with metabolic, immune, and clinical symptoms. Finally, different interventions (lifestyle interventions, lifestyle interventions + oral probiotic, lifestyle interventions+ compound oral contraceptives) would be used to explore the change of gut microbiome in PCOS patients. This research will not only help the understanding of the pathophysiology of PCOS, but also provide a reference for the selection of clinical treatment options.

Detailed Description

1. Data quality assurance: ① all inspections and measurements will be performed by either the hospital or the sequencing company personnel according to standard operating procedures (SOPs), except for saliva and stool samples, which will be self-collected by patients. For sample collection, we will provide text descriptions of the SOPs as well as video instruction. Designated staff will be assigned for support and can be contacted if participants have any queries concerning sample collection; ② a case report form (CRF) will be prepared according to the current SOPs, and detailed instructions will be provided to ensure consistency in data collection. At the same time, each CRF will be properly stored at least 5 years for verification and backtracking; ③ all experimental data will be logged into the database to ensure information accuracy based on the existing data; ④ we will keep the contact information of each participant, remind them of precautions during participation, and conduct regular follow-ups.

2. Sample size determination: The number of participants is based on comparable sample sizes in the literature. In this trial, there will be 50 healthy individuals (control group) and 150 PCOS (polycystic ovary syndrome) patients. The 150 PCOS patients will be randomly assigned to three intervention groups. This sample size accounts for a plausible insufficiency of data caused by patient dropouts and withdrawals before the study is completed. The participation cycle is of approximately four months, followed by a 2-year follow-up.

3. Metagenomic sequencing technology Metagenomic sequencing is the main technique used in this study. Metagenomics, also known as economics, was first proposed by Handelman and studies the molecular composition of microbial populations, their interactions, and gene functions.

In medicine, metagenomics compares the structural and functional changes of human microbial communities under normal and disease states. It can analyze the diversity and the functional differences of microbial communities from healthy individuals and from patients with diseases, thus determine how diseases relate to changes in the microbial communities and in their respective metabolic networks. Therefore, metagenomics provides theoretical evidence for disease prevention, detection, and treatment. At present, the internationally renowned Human Microbiome Project (HMP, http://www.hmpdacc.org/) and the Metagenomics of the Human Intestinal Tract (MetaHIT) are typical applications of metagenomics in medicine.

[Metagenomic species, genes, and functional annotation]

① Data quality control: the sequenced raw data will contain a certain amount of low-quality data, so quality control must be performed. Only high-quality data can correctly reflect the actual occurrence of microorganisms in the sample.

② Metagenome assembly: based on Clean Data, individual samples will be assembled separately at first, then reads that do not participate in the assembling above will be combined and mixed for assembly. This will increase the sequencing depth of low-abundance species in each sample and provide more sequencing information for each species.

③ Gene prediction: MetaGeneMark will be used for gene prediction based on single samples and mixed-assembled scaftigs. The redundancy of all predicted genes will be reduced to obtain a Uniq gene set. Then, the Clean Data of each sample will be compared to the gene set and the abundance of the gene set will be determined for each sample.

④ Species annotation: Clean Data will be used for quality control. It will be compared with an annotated according to reference genome databases of bacteria, archaea, viruses, and fungi from NCBI. A species abundance table will be obtained for each sample at different classification levels.

⑤ Functional annotation: functional annotation and abundance statistics will be based on the Uniq gene set and the KEGG database.

Conditions

Polycystic Ovary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Health control group

Participants are healthy women and there are no interventions.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Lifestyle interventions group

Participants are PCOS patients and only will be given lifestyle interventions.

Group Type: EXPERIMENTAL

Probiotic Agent

Intervention Type: DRUG

Patients have to take a probiotic powder (product name: Tangwen Tai, lactobacillus plantarum LP45 + Lactobacillus acidophilus La28 + Bifidobacterium lactobacillus BAL531) twice a day for three months.

Oral contraceptive

Intervention Type: DRUG

The patient needs to take drospirenone ethinyl estradiol tablets (trade name: Yousi Yue) 1 tablet daily for 3 months.

Probiotic Agent group

Participants are PCOS patients and will be given lifestyle interventions + Probiotic Agent interventions.

Group Type: EXPERIMENTAL

Lifestyle intervention

Intervention Type: BEHAVIORAL

1. Balance the diet;

2. Limit high-calorie and high-fat food intake, reduce eating out, and establish regular eating habits;

3. Monitor body weight, avoid sedentary, get more sun and regular activities;

4. Mental health regulation.

Oral contraceptive

Intervention Type: DRUG

The patient needs to take drospirenone ethinyl estradiol tablets (trade name: Yousi Yue) 1 tablet daily for 3 months.

Oral contraceptive group

Participants are PCOS patients and will be given lifestyle intervention + Oral contraceptive interventions.

Group Type: EXPERIMENTAL

Lifestyle intervention

Intervention Type: BEHAVIORAL

1. Balance the diet;

2. Limit high-calorie and high-fat food intake, reduce eating out, and establish regular eating habits;

3. Monitor body weight, avoid sedentary, get more sun and regular activities;

4. Mental health regulation.

Probiotic Agent

Intervention Type: DRUG

Patients have to take a probiotic powder (product name: Tangwen Tai, lactobacillus plantarum LP45 + Lactobacillus acidophilus La28 + Bifidobacterium lactobacillus BAL531) twice a day for three months.

Interventions

Lifestyle intervention

1. Balance the diet;

2. Limit high-calorie and high-fat food intake, reduce eating out, and establish regular eating habits;

3. Monitor body weight, avoid sedentary, get more sun and regular activities;

4. Mental health regulation.

Intervention Type: BEHAVIORAL

Probiotic Agent

Patients have to take a probiotic powder (product name: Tangwen Tai, lactobacillus plantarum LP45 + Lactobacillus acidophilus La28 + Bifidobacterium lactobacillus BAL531) twice a day for three months.

Intervention Type: DRUG

Oral contraceptive

The patient needs to take drospirenone ethinyl estradiol tablets (trade name: Yousi Yue) 1 tablet daily for 3 months.

Intervention Type: DRUG

Other Intervention Names

Tangwen Tai; Drospirenone and Ethinylestradiol Tablets; Yousi Yue

Eligibility Criteria

Inclusion Criteria

1. Conforms to the 2003 Rotterdam classic PCOS diagnostic criteria.

1. sparse ovulation or anovulation;

2. clinical manifestations of high androgen and/or hyperandrogenism;

3. ovarian polycystic changes: ultrasound suggests one or both sides of the ovary with a diameter of 2-9 mm follicles ≥ 12, and / or ovarian volume ≥ 10 ml;

2 out of 3 items, and exclude other high androgen causes, such as congenital adrenal hyperplasia, Cushing's syndrome, and androgen-secreting tumors;

2. Age: 18-45 years old.

Exclusion Criteria

1. pregnancy;

2. menopause;

3. adrenal abnormalities;

4. thyroid dysfunction;

5. taking antibiotics for the past 3 months;

6. is taking oral contraceptive treatment;

7. basic diseases of the gastrointestinal tract (ulcerative colitis, Crohn's disease, inflammatory bowel disease, etc.);

8. history of smoking;

9. BMI<18kg/m2.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Peking Union Medical College

OTHER

Sponsor Role: collaborator

Peking Union Medical College Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Rong Chen, Ph. D.

Role: STUDY_DIRECTOR

Beijing Union Medical College Hospital

Locations

Peking Union Medical College Hospital

Beijing, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Rong Chen, Ph. D.

Role: CONTACT

chenrongpumch@163.com

(86-10)-69155012

Xu Zhang, master

Role: CONTACT

zhangxu_5050@163.com

Facility Contacts

Rong Chen, Ph. D

Role: primary

chenrongpumch@163.com

(86-10)-69155012

Xu Zhang, Master

Role: backup

zhangxu_5050@163.com

References

Alvarez-Blasco F, Luque-Ramirez M, Escobar-Morreale HF. Diet composition and physical activity in overweight and obese premenopausal women with or without polycystic ovary syndrome. Gynecol Endocrinol. 2011 Dec;27(12):978-81. doi: 10.3109/09513590.2011.579658. Epub 2011 May 24.

Reference Type: BACKGROUND

PMID: 21609197 (View on PubMed)

Tremellen K, Pearce K. Dysbiosis of Gut Microbiota (DOGMA)--a novel theory for the development of Polycystic Ovarian Syndrome. Med Hypotheses. 2012 Jul;79(1):104-12. doi: 10.1016/j.mehy.2012.04.016. Epub 2012 Apr 27.

Reference Type: BACKGROUND

PMID: 22543078 (View on PubMed)

Liu R, Zhang C, Shi Y, Zhang F, Li L, Wang X, Ling Y, Fu H, Dong W, Shen J, Reeves A, Greenberg AS, Zhao L, Peng Y, Ding X. Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome. Front Microbiol. 2017 Feb 28;8:324. doi: 10.3389/fmicb.2017.00324. eCollection 2017.

Reference Type: BACKGROUND

PMID: 28293234 (View on PubMed)

Guo Y, Qi Y, Yang X, Zhao L, Wen S, Liu Y, Tang L. Association between Polycystic Ovary Syndrome and Gut Microbiota. PLoS One. 2016 Apr 19;11(4):e0153196. doi: 10.1371/journal.pone.0153196. eCollection 2016.

Reference Type: RESULT

PMID: 27093642 (View on PubMed)

Torres PJ, Siakowska M, Banaszewska B, Pawelczyk L, Duleba AJ, Kelley ST, Thackray VG. Gut Microbial Diversity in Women With Polycystic Ovary Syndrome Correlates With Hyperandrogenism. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1502-1511. doi: 10.1210/jc.2017-02153.

Reference Type: RESULT

PMID: 29370410 (View on PubMed)

Other Identifiers

81871141

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

JS-1691

Identifier Type: -

Identifier Source: org_study_id