Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Syndrome

Polycystic Ovary Syndrome

Dysbiosis

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Natriuretic Agents

All Drugs and Chemicals

Reproductive Control Agents

Other Dietary Supplements

Drospirenone

Ethinyl Estradiol

Estradiol 17 beta-cypionate

Estradiol 3-benzoate

Estradiol

Polyestradiol phosphate

Contraceptive Agents

Drospirenone and ethinyl estradiol combination

Contraceptives, Oral

Contraceptive Agents, Female

Mineralocorticoid Receptor Antagonists

Mineralocorticoids

Hormones

Hormone Antagonists

Diuretics

Diuretics, Potassium Sparing

Contraceptives, Oral, Hormonal

Contraceptive Agents, Hormonal

Estrogens

Acidophilus

Bifidobacterium

Participants are healthy women and there are no interventions.

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

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

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

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.

Lifestyle intervention

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.

Probiotic Agent

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

Oral contraceptive

Rong Chen, Ph. D.

Xu Zhang, master

Rong Chen, Ph. D

Xu Zhang, Master

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.

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.

This study will collect 50 healthy participants and 150 PCOS participants. At the same time, 150 patients with PCOS will be randomly divided into the lifestyle intervention group, lifestyle interventions + Probiotic Agent group, lifestyle intervention + oral contraceptive group by random number table method.

Polycystic ovary syndrome (PCOS) is a syndrome of endocrine disorders characterized by sparse ovulation or anovulation, high androgen or insulin resistance, and polycystic ovary. PCOS is a woman-specific disease, so participants must be women.

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

The Role of Dysbiosis of Gut Microbiota in the Pathogenesis of Polycystic Ovary Syndrome.

According to national laws and regulations, human genetic resources may not be provided abroad.

Based on the gene and species composition of each sample, the Chao1 and Shannon indexes, as well as the observed OTUs (operational taxonomic units), will be calculated in order to identify the differences in gene and species diversity for each group.

The Spearman correlation coefficient between genes will be calculated, and genes with strong correlation will be grouped into one cluster, as a CAG. The abundance of CAGs in each sample will be determined Furthermore, the significantly enriched species in the control and PCOS groups will be enumerated for network display.

The LEfSe discriminant analysis will be used to screen for significant differences between groups. The dimensionality reduction will be implemented by LDA, and the impact of function difference will be evaluated to obtain the LDA score and identify significantly different functions between groups.

For the obtained species, genes, or functions with significant difference, the correlation between them and clinical indicators will be calculated, and key biomarkers with significant and strong correlation will be identified.

Use glucose tolerance and insulin test (75gOGTT+insulin) to assess whether the patient has insulin resistance, as well as the level of insulin resistance.

Six-sex-hormone tests, one of the clinical examination items, will be performed to measure androgen levels in the subjects.

Peking Union Medical College

Peking Union Medical College Hospital

Hypoglycemic Agents

Gastrointestinal Agents

Insulin

Insulin, Globin Zinc

Metformin

Glucagon

Glucagon-Like Peptide 1

Biguanides

Group no 1(26 patients) Metformin tablets at a dose of 500mg BD for 12 weeks

Group no 2(26 patients): will be given probiotics alone at a dose of 180mg B.D for 12 weeks

Group no 3(26 patients): will be given metformin 500mg B.D and probiotics 180mgram O.D. for 12 week

Probiotics are live microorganisms, which when administered in adequate amounts confer a health benefit effects on the host.

Many clinical trials have been done on probiotic which show its use as a single or as an adjuvant drug therapy for various diseases with no or rare side effects. It is now frequently used agent for various diseases.

Apart from this many studies have been published related to effects of probiotics on PCOS, which shows effectiveness of probiotics when used for 8 to 12 weeks with no adverse effects observed by these micro-organisms but none of the study have compare it with standarad drug

Metformin, an insulin sensitizer, is an oral biguanide that is most commonly prescribed for the management of type II diabetes mellitus and various symptoms of PCOS. It is derived from the extract of Galega officinalis.

It remediates hyperglycemia through activation of AMPK which stimulates glucose uptake and its consumption; promote fatty acid oxidation along with suppression of hepatic glucose production. It is also involved in increase GLUT4 translocation in the muscle and fat leading to decrease hepatic lipid synthesis. Moreover, It is also reported that it decreases gut absorption of glucose by increasing the glucagon-like peptide-1 (GLP-1) in this way, it reduces the insulin requirement too.All of these actions of metformin decrease insulin resistance and thus improve the state of hyperinsulinemia associated with diabetes and PCOS

Dr.Urooj Zafar, M.Phil

Polycystic ovary syndrome (PCOS) is a common gynecological state worldwide characterized by numerous small cysts in the ovaries mainly due to the imbalance of endocrine hormones in premenopausal women. Metformin is long being used for different symptoms of PCOS along with other medication. This study involves the assessment of different parameters of PCOS.

Polycystic ovary syndrome (PCOS) is a hormonal disorder affecting the women of reproductive age. It is a heterogeneous health condition that affects 1 in every 10 women of childbearing age. Women of all races and ethnicities are at risk for PCOS, but risk increases multiple folds if the BMI is greater than 30kg/m2. The common signs and symptoms, the women usually represent with are menstrual irregularities, hyperandrogenemia and multiple cysts in ovaries. The exact cause of PCOS is still unknown but genetic and obesity is considered to be the most common cause.

Metformin has been considered as the first line agent for the treatment of non-insulin dependent diabetes mellitus and up till now it has been used as a first line drug for PCOS. Despite its beneficial effects in PCOS it has several adverse effects. Moreover, patients usually seek two or more drugs along with metformin to relieve maximum symptoms of PCOS like for ovulation clomiphene citrate must be given etc. So there is a need of novel and comprehensive agent that can prove to be effective in improving maximum symptoms of this disease. Probiotics have received renewed attention in the 21st century through research studies. World Health Organization's (WHO) 2001 defines probiotics as live micro-organisms that, when administered in adequate amounts, confer a health benefit on the host. In recent year it has shown tremendous promising effect in treatment of different diseases like diarrhea, gingivitis and obesity etc with negligible side effects.

In this context the investigators are going to evaluate and compare the effects of probiotics, metformin and their combination therapy in treatment of various symptoms of PCOS.60 newly diagnosed PCOS patient will be assigned in the open label randomized clinical trial. As mentioned above patients will be divided into three groups with 20 patients each. In group 1, the dosage of metformin will be 500mg B.D and 2 gm of probiotic sachet O.D, the second group will be given metformin 500mg B.D. and the third group will be 2mg of probiotics B.D. It would be a follow-up study that would be conducted in Gynecology OPD of Tertiary Care Hospital

Comparison of Probiotics, Metformin & Their Combination Therapy in the Treatment of PCOS

Comparison of Probiotics, Metformin and Their Combination Therapy in Improving Symptoms of Polycystic Ovarian Syndrome.̎- A Randomized Clinical Trial

Fasting serum glucose:

The blood sample for FBS will be collected on day 2 or 3 of the menses. The blood samples will be taken before the start and at the end of the treatment.

fasting glucose 80-100 mg/dl

Androgens:

The concentration of these hormones will be evaluated at the baseline and at the end of treatment usually in the morning between 8:00 am to 9:00 am after overnight fasting

Serum testosterone:15 and 70 ng/dL

Ovary cyst size:

The size of the cyst will be measured before the start and at the end of the study, considering 12 or more follicles in at least 1 ovary or both-measuring 2-9 mm in diameter-or a total ovarian volume greater than 10 cm3

LH

The concentration of this endocrine hormones is determined will be obtained on day 2 or 3 of the normal menstruation cycle and at any time in women with amenorrhea.

LH: 1.9 to 12.5 IU/L

Fasting serum insulin:

The sample is collected after fasting of 12 to 14 hours will be measured before and after intervention

fasting insulin \< 25 mIU/L

Lipid profile:

1. Total cholesterol
2. LDL
3. HDL
4. Triglyceride

The serum lipid concentrations will be evaluated spectrophotometrically by means of commercial kits at baseline and at the end of the study

Total cholesterol \< 200

Triglyceride: \<150 mg/dl

HDL: \> 60mg/ dl

LDL: \< 130mg /dl

The concentration of this endocrine hormones is determined will be obtained on day 2 or 3 of the normal menstruation cycle and at any time in women with amenorrhea.

LH: 4.5 to 21.5 IU/L

LH:FSH The serum levels of FSH:LH ratio will be assessed before the start and at the end of the management on day 2 or 3 of the normal menses and at any time in women with amenorrhea.

1.5:1

Weight:

The body weight of the females will be recorded at baseline and at the end of the treatment with the help of weighing machine in kg.

Menstrurational irregularities:

All study participants will be asked about menstruation irregularities at the time of enrollment.They will also be enquired about for long they have their cycles have been disturbed.They will be asked to maintain their cycle dates as well.

Hirsutism:

History and physical examination, including pelvic examination at the start and at the end of treatment using the Ferriman-Gallwey scale for hirsutism.

Acne:

Acne score will be taken at baseline and at the end of the treatment through the Global Acne grading system.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Role of Dysbiosis of Gut Microbiota in the Pathogenesis of PCOS.	NCT03843736	Polycystic Ovar...	Lifestyle inter... Probiotic Agent Oral contracept...	18 Years - 45 Years	Peking Union Medical College Hospital
Comparison of Probiotics, Metformin & Their Combination Therapy in the Treatment of PCOS	NCT04009603	Polycystic Ovar...	Probiotic Agent Metformin	18 Years - 40 Years	Ziauddin University
Comparison of Probiotics, Metformin & Their Combination Therapy in the Treatment of PCOS	NCT04009603	Polycystic Ovar...	Probiotic Agent Metformin	18 Years - 40 Years	Ziauddin University
The Role of Dysbiosis of Gut Microbiota in the Pathogenesis of PCOS.	NCT03843736	Polycystic Ovar...	Lifestyle inter... Probiotic Agent Oral contracept...	18 Years - 45 Years	Peking Union Medical College Hospital

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